Dihydropyrimidin-2(1H)-one compounds as S-nitrosoglutathione reductase inhibitors

ABSTRACT

The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/262,915, filed Apr. 28, 2014. U.S. application Ser. No. 14/262,915 isa divisional application of U.S. application Ser. No. 13/496,799, filedApr. 27, 2012, now U.S. Pat. No. 8,741,915. U.S. application Ser. No.13/496,799 is a 35 U.S.C. §371 national phase application ofPCT/US2010/050164, filed Sep. 24, 2010 (WO 2011/038204), which claimsthe benefit of U.S. Provisional Application Ser. No. 61/245,859, filedSep. 25, 2009. Each of these applications is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel dihydropyrimidin-2(1H)-onecompounds, pharmaceutical compositions comprising such compounds, andmethods of making and using the same. These compounds are useful asinhibitors of S-nitrosoglutathione reductase (GSNOR).

BACKGROUND

The chemical compound nitric oxide is a gas with chemical formula NO. NOis one of the few gaseous signaling molecules known in biologicalsystems, and plays an important role in controlling various biologicalevents. For example, the endothelium uses NO to signal surroundingsmooth muscle in the walls of arterioles to relax, resulting invasodilation and increased blood flow to hypoxic tissues. NO is alsoinvolved in regulating smooth muscle proliferation, platelet function,neurotransmission, and plays a role in host defense. Although nitricoxide is highly reactive and has a lifetime of a few seconds, it canboth diffuse freely across membranes and bind to many molecular targets.These attributes make NO an ideal signaling molecule capable ofcontrolling biological events between adjacent cells and within cells.

NO is a free radical gas, which makes it reactive and unstable, thus NOis short lived in vivo, having a half life of 3-5 seconds underphysiologic conditions. In the presence of oxygen, NO can combine withthiols to generate a biologically important class of stable NO adductscalled S-nitrosothiols (SNO's). This stable pool of NO has beenpostulated to act as a source of bioactive NO and as such appears to becritically important in health and disease, given the centrality of NOin cellular homeostasis (Stamler et al., Proc. Natl. Acad. Sci. USA,89:7674-7677 (1992)). Protein SNO's play broad roles in cardiovascular,respiratory, metabolic, gastrointestinal, immune and central nervoussystem function (Foster et al., 2003, Trends in Molecular MedicineVolume 9, Issue 4, April 2003, pages 160-168). One of the most studiedSNO's in biological systems is S-nitrosoglutathione (GSNO) (Gaston etal., Proc. Natl. Acad. Sci. USA 90:10957-10961 (1993)), an emerging keyregulator in NO signaling since it is an efficient trans-nitrosatingagent and appears to maintain an equilibrium with other S-nitrosatedproteins (Liu et al., Nature, 410:490-494 (2001)) within cells. Giventhis pivotal position in the NO-SNO continuum, GSNO provides atherapeutically promising target to consider when NO modulation ispharmacologically warranted.

In light of this understanding of GSNO as a key regulator of NOhomeostasis and cellular SNO levels, studies have focused on examiningendogenous production of GSNO and SNO proteins, which occurs downstreamfrom the production of the NO radical by the nitric oxide synthetase(NOS) enzymes. More recently there has been an increasing understandingof enzymatic catabolism of GSNO which has an important role in governingavailable concentrations of GSNO and consequently available NO andSNO's.

Central to this understanding of GSNO catabolism, researchers haverecently identified a highly conserved S-nitrosoglutathione reductase(GSNOR) (Jensen et al., Biochem J., 331:659-668 (1998); Liu et al.,(2001)). GSNOR is also known as glutathione-dependent formaldehydedehydrogenase (GS-FDH), alcohol dehydrogenase 3 (ADH-3) (Uotila andKoivusalo, Coenzymes and Cofactors, D. Dolphin, ed. pp. 517-551 (NewYork, John Wiley & Sons, 1989)), and alcohol dehydrogenase 5 (ADH-5).Importantly GSNOR shows greater activity toward GSNO than othersubstrates (Jensen et al., 1998; Liu et al., 2001) and appears tomediate important protein and peptide denitrosating activity inbacteria, plants, and animals. GSNOR appears to be the majorGSNO-metabolizing enzyme in eukaryotes (Liu et al., 2001). Thus, GSNOcan accumulate in biological compartments where GSNOR activity is low orabsent (e.g. airway lining fluid) (Gaston et al., 1993).

Yeast deficient in GSNOR accumulate S-nitrosylated proteins which arenot substrates of the enzyme, which is strongly suggestive that GSNOexists in equilibrium with SNO-proteins (Liu et al., 2001). Preciseenzymatic control over ambient levels of GSNO and thus SNO-proteinsraises the possibility that GSNO/GSNOR may play roles across a host ofphysiological and pathological functions including protection againstnitrosative stress wherein NO is produced in excess of physiologicneeds. Indeed, GSNO specifically has been implicated in physiologicprocesses ranging from the drive to breathe (Lipton et al., Nature,413:171-174 (2001)) to regulation of the cystic fibrosis transmembraneregulator (Zaman et al., Biochem Biophys Res Commun, 284:65-70 (2001),to regulation of vascular tone, thrombosis and platelet function (deBelder et al., Cardiovasc Res. 1994 May; 28(5):691-4. (1994); Z.Kaposzta, A et al., Circulation; 106(24): 3057-3062, 2002) as well ashost defense (de Jesus-Berrios et al., Curr. Biol., 13:1963-1968(2003)). Other studies have found that GSNOR protects yeast cellsagainst nitrosative stress both in vitro (Liu et al., 2001) and in vivo(de Jesus-Berrios et al., 2003).

Collectively data suggest GSNOR as a primary physiological ligand forthe enzyme S-nitrosoglutathione reductase (GSNOR), which catabolizesGSNO and consequently reduces available SNO's and NO in biologicalsystems (Liu et al., 2001), (Liu et al., Cell, (2004), 116(4), 617-628),and (Que et al., Science, 2005, 308, (5728):1618-1621). As such, thisenzyme plays a central role in regulating local and systemic bioactiveNO. Since perturbations in NO bioavailability has been linked to thepathogenesis of numerous disease states, including hypertension,atherosclerosis, thrombosis, asthma, gastrointestinal disorders,inflammation and cancer, agents that regulate GSNOR activity arecandidate therapeutic agents for treating diseases associated withnitric oxide imbalance.

Currently, there is a great need in the art for diagnostics,prophylaxis, ameliorations, and treatments for medical conditionsrelating to increased NO synthesis and/or increased NO bioactivity. Inaddition, there is a significant need for novel compounds, compositionsand methods for preventing, ameliorating, or reversing otherNO-associated disorders. The present invention satisfies these needs.

SUMMARY

The present invention provides novel dihydropyrimidin-2(1H)-onecompounds. These compounds are useful as S-nitrosoglutathione reductase(“GSNOR”) inhibitors. The invention encompasses pharmaceuticallyacceptable salts, prodrugs, and metabolites of the described compounds.Also encompassed by the invention are pharmaceutical compositionscomprising at least one compound of the invention and at least onepharmaceutically acceptable carrier.

The compositions of the present invention can be prepared in anysuitable pharmaceutically acceptable dosage form.

The present invention provides a method for inhibitingS-nitrosoglutathione reductase in a subject in need thereof. Such amethod comprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one GSNOR inhibitor or apharmaceutically acceptable salt thereof, a prodrug or metabolitethereof, in combination with at least one pharmaceutically acceptablecarrier. The GSNOR inhibitor can be a novel compound according to theinvention, or it can be a known compound which previously was not knownto be an inhibitor of GSNOR.

The present invention also provides a method of treating a disorderameliorated by NO donor therapy in a subject in need thereof. Such amethod comprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one GSNOR inhibitor or apharmaceutically acceptable salt thereof, a prodrug, or metabolitethereof, in combination with at least one pharmaceutically acceptablecarrier. The GSNOR inhibitor can be a novel compound according to theinvention, or it can be a known compound which previously was not knownto be an inhibitor of GSNOR.

The present invention also provides a method of treating a cellproliferative disorder in a subject in need thereof. Such a methodcomprises administering a therapeutically effective amount of apharmaceutical composition comprising at least one GSNOR inhibitor or apharmaceutically acceptable salt thereof, a prodrug, or metabolitethereof, in combination with at least one pharmaceutically acceptablecarrier. The GSNOR inhibitor can be a novel compound according to theinvention, or it can be a known compound which previously was not knownto be an inhibitor of GSNOR.

The methods of the invention encompass administration with one or moresecondary active agents. Such administration can be sequential or in acombination composition.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described below. All publiclyavailable publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present specification, includingdefinitions, will control.

Both the foregoing summary and the following detailed description areexemplary and explanatory and are intended to provide further details ofthe compositions and methods as claimed. Other objects, advantages, andnovel features will be readily apparent to those skilled in the art fromthe following detailed description.

DETAILED DESCRIPTION A. Overview of the Invention

Until recently, S-nitrosoglutathione reductase (GSNOR) was known tooxidize the formaldehyde glutathione adduct, S-hydroxymethylglutathione.GSNOR has since been identified in a variety of bacteria, yeasts, plantsand animals and is well conserved. The proteins from E. coli, S.cerevisiae and mouse macrophages share over 60% amino acid sequenceidentity. GSNOR activity (i.e., decomposition of S-nitrosoglutathionewhen NADH is present as a required cofactor) has been detected in E.coli, in mouse macrophages, in mouse endothelial cells, in mouse smoothmuscle cells, in yeasts, and in human HeLa, epithelial and monocytecells. Human GSNOR nucleotide and amino acid sequence information can beobtained from the National Center for Biotechnology Information (NCBI)databases under Accession Nos. M29872, NM_(—)000671. Mouse GSNORnucleotide and amino acid sequence information can be obtained from NCBIdatabases under Accession Nos. NM_(—)007410. In the nucleotide sequence,the start site and stop site are underlined. CDS designates codingsequence. SNP designates single nucleotide polymorphism. Other relatedGSNOR nucleotide and amino acid sequences, including those of otherspecies, can be found in U.S. Patent Application 2005/0014697.

In accord with the present invention, GSNOR has been shown to functionin vivo and in vitro to metabolize S-nitrosoglutathione (GSNO) andprotein S-nitrosothiols (SNOs) to modulate NO bioactivity, bycontrolling the intracellular levels of low mass NO donor compounds andpreventing protein nitrosylation from reaching toxic levels.

Based on this, it follows that inhibition of this enzyme potentiatesbioactivity in all diseases in which NO donor therapy is indicated,inhibits the proliferation of pathologically proliferating cells, andincreases NO bioactivity in diseases where this is beneficial.

The present invention provides pharmaceutical agents that are potentinhibitors of GSNOR. In particular, provided are substituteddihydropyrimidin-2(1H)-one analogs having the structures depicted below(Formula I), or a pharmaceutically acceptable salt, stereoisomer, orprodrug thereof.

whereinX is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl, each having 6 members orless in the ring;Y is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₄-C₆ cycloalkyl, substituted C₄-C₆cycloalkyl, heterocyclyl, and substituted heterocyclyl;Z is selected from the group consisting of O, S and NR₇;R₁, R₂ and R₇ are independently selected from the group consisting ofhydrogen, and C₁-C₆ alkyl;R₃ is selected from the group consisting of hydrogen, nitro, cyano,carboxy, carbamoyl, methylsulfonamido, fluoro, chloro, bromo, hydroxy,methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy,—C(NH)NHOH, sulfonic acid, and acetyl;R₄ is selected from the group consisting of hydroxy, carboxy, andtetrazol-5-yl; or optionally R₃ and R₄, taken together can form aheterocycle;R₅ is selected from the group consisting of hydrogen, hydroxy, carboxy,chloro, fluoro, cyano, —O(CH₂)₁₋₆NMe₂, C₁-C₆ alkyl, —O(CH₂)₁₋₆OCH₃,—O(CH₂)₁₋₆OH, acetyl, CF₃, and C₁-C₆ alkoxy;or optionally R₄ and R₅, taken together can form a heterocycle; andR₆ is selected from the group consisting of hydrogen and hydroxy.As used in this context, the term “analog” refers to a compound havingsimilar chemical structure and function as compounds of Formula I thatretains the dihydropyrimidin-2(1H)-one ring.

Some dihydropyrimidin-2(1H)-one analogs of the invention can also existin various isomeric forms, including configurational, geometric andconformational isomers, as well as existing in various tautomeric forms,particularly those that differ in the point of attachment of a hydrogenatom. As used herein, the term “isomer” is intended to encompass allisomeric forms of a compound including tautomeric forms of the compound.

Illustrative compounds having asymmetric centers can exist in differentenantiomeric and diastereomeric forms. A compound can exist in the formof an optical isomer or a diastereomer. Accordingly, the inventionencompasses compounds in the forms of their optical isomers,diastereomers and mixtures thereof, including racemic mixtures.

It should be noted that if there is a discrepancy between a depictedstructure and a name given to that structure, the depicted structurecontrols. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold, wedged,or dashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of the described compound.

B. S-Nitrosoglutathione Reductase Inhibitors

1. Inventive Compounds

In one of its aspects the present invention provides a compound having astructure shown in Formula I, or a pharmaceutically acceptable salt,stereoisomer, or prodrug thereof:

whereinX is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl, each having 6 members orless in the ring;Y is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₄-C₆ cycloalkyl, substituted C₄-C₆cycloalkyl, heterocyclyl, and substituted heterocyclyl;Z is selected from the group consisting of O, S and NR₇;R₁, R₂ and R₇ are independently selected from the group consisting ofhydrogen, and C₁-C₆ alkyl;R₃ is selected from the group consisting of hydrogen, nitro, cyano,carboxy, carbamoyl, methylsulfonamido, fluoro, chloro, bromo, hydroxy,methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy,—C(NH)NHOH, sulfonic acid, and acetyl;R₄ is selected from the group consisting of hydroxy, carboxy, andtetrazol-5-yl; or optionally R₃ and R₄, taken together can form aheterocycle;R₅ is selected from the group consisting of hydrogen, hydroxy, carboxy,chloro, fluoro, cyano, —O(CH₂)₁₋₆NMe₂, C₁-C₆ alkyl, —O(CH₂)₁₋₆OCH₃,—O(CH₂)₁₋₆OH, acetyl, CF₃, and C₁-C₆ alkoxy;or optionally R₄ and R₅, taken together can form a heterocycle; andR₆ is selected from the group consisting of hydrogen and hydroxy.

In a further aspect of the invention, R₁, R₂ and R₇ are independentlyselected from the group consisting of hydrogen and methyl; R₃ isselected from the group consisting of hydrogen, nitro, cyano, carboxy,carbamoyl, methylsulfonamido, fluoro, chloro, bromo, hydroxy,methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy,—C(NH)NHOH, sulfonic acid, and acetyl; R₄ is selected from the groupconsisting of hydroxy, carboxy, and tetrazol-5-yl; R₅ is selected fromthe group consisting of hydrogen, hydroxy, carboxy, chloro, fluoro,cyano, —O(CH₂)₂NMe₂, C₁-C₆ alkyl, —O(CH₂)₂OCH₃, —O(CH₂)₂OH, acetyl, CF₃,methoxy, ethoxy, isopropoxy, and n-propoxy; and R₆ is hydrogen.

In a further aspect of the invention, R₁, R₂ and R₇ are independentlyselected from the group consisting of hydrogen and methyl; R₃ isselected from the group consisting of nitro, cyano, carboxy, carbamoyl,methylsulfonamido, fluoro, chloro, bromo, hydroxy, methylsulfonyl, andmethylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid,and acetyl; R₄ is selected from the group consisting of hydroxy,carboxy, and tetrazol-5-yl; R₅ is selected from the group consisting ofhydrogen, hydroxy, carboxy, chloro, fluoro, cyano, —O(CH₂)₂NMe₂, C₁-C₆alkyl, —O(CH₂)₂OCH₃, —O(CH₂)₂OH, acetyl, CF₃, methoxy, ethoxy,isopropoxy, and n-propoxy; and R₆ is hydrogen.

In a further aspect of the invention, suitable identities for X include,but are not limited to phenyl, substituted phenyl, thiophen-yl,substituted thiophen-yl, thiazol-yl, substituted thiazol-yl, pyrazin-yl,substituted pyrazin-yl, pyridin-yl, and substituted pyridin-yl,cyclohexyl, and substituted cyclohexyl.

In a further aspect of the invention, suitable identities for X include,but are not limited to, phenyl, thiophen-2-yl, thiophen-3-yl,thiazol-2-yl, 2-fluorophenyl, p-tolyl, m-tolyl, biphenyl-4-yl,4-methoxyphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl,3,4-dimethoxyphenyl, 4-bromophenyl, o-tolyl, 4-chlorophenyl,2-chlorophenyl, 3-cyanophenyl, 3,4-difluorophenyl, 4-cyanophenyl,3-carbamoylphenyl, pyrazin-2-yl, biphenyl-3-yl, 2-cyanophenyl,pyridin-4-yl, and pyridin-3-yl, 4-(dimethylamino)phenyl, 3-fluorophenyl,3-ethylphenyl, and cyclohexyl.

In a further aspect of the invention, suitable identities for Y include,but are not limited to phenyl, substituted phenyl, thiophen-yl,substituted thiophen-yl, thiazol-yl, substituted thiazol-yl, pyrazin-yl,substituted pyrazin-yl, pyridin-yl, substituted pyridin-yl, furan-yl,substituted furan-yl, benzo[d][1,3]dioxol-yl, substitutedbenzo[d][1,3]dioxol-yl, imidazol-yl, substituted imidazol-yl,naphthalen-yl, substituted naphthalen-yl, pyrrol-yl, substitutedpyrrol-yl, pyrazol-yl, substituted pyrazol-yl, tetrahydrofuran-yl,substituted tetrahydrofuran-yl, cyclopentyl, substituted cyclopentyl,cyclohexyl, and substituted cyclohexyl.

In a further aspect of the invention, suitable identities for Y include,but are not limited to, phenyl, 3-methoxyphenyl, p-tolyl,4-methoxyphenyl, 3,5-dichlorophenyl, 3-fluorophenyl, 4-bromophenyl,biphenyl-4-yl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl,3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3,4-dichlorophenyl, 4-hydroxyphenyl, 2,4-difluorophenyl, furan-3-yl,2-chlorophenyl, 3-cyanophenyl, 4-(dimethylamino)phenyl, 2-fluorophenyl,4-morpholinophenyl, 4-aminophenyl, naphthal-2-yl,benzo[d][1,3]dioxol-5-yl, 4-cyanophenyl, naphthal-3-yl, naphthal-4-yl,4-acetamidophenyl, thiophen-2-yl, thiophen-3-yl,1-methyl-1H-imidazol-4-yl, naphthalene-1-yl, methyl phenylcarbamate, andnaphthalene-2-yl, 4-(methanesulfonamido)phenyl, 1H-pyrrol-3-yl,1-(phenylsulfonyl)-1H-pyrrol-3-yl, furan-2-yl,4-(trifluoromethyl)phenyl, o-tolyl, 1-methyl-1H-pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 3-chloro-5-fluorophenyl, 3-hydroxyphenyl,pyrazin-2-yl, quinolin-6-yl, isoquinolin-6-yl, 1-methyl-1H-pyrazol-5-yl,tetrahydrofuran-2-yl, cyclopentyl, tetrahydrofuran-3-yl, and cyclohexyl.

In a further aspect of the invention, suitable compounds of formula Iinclude, but are not limited to:

-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   (S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   (S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione;-   4-(4-hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3,4-dihydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(2-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-m-tolyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;-   5-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3,5-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluoro-4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1,3-dimethyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;-   6-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3-chloro-4-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3,5-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-3-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide;-   3-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;-   6-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(2-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-morpholinophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyrazin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   5-(biphenyl-3-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(benzo[d][1,3]dioxol-5-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-3-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;-   4-(3-ethoxy-5-fluoro-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   (R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   (S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;-   2-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;-   7-ethoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one;-   N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)acetamide;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;-   N-(3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;-   N-(2-hydroxy-3-methoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;-   3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-imidazol-4-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-1-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide;-   methyl    4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenylcarbamate;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(4-hydroxy-3-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   5-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;-   1,1′-(2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-1,3-phenylene)diethanone;-   4-(4-hydroxy-3-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;-   2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-bromo-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;-   4-(4-hydroxy-3-isopropoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-(methylsulfonyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-(methylsulfinyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-ethoxy-2-hydroxy-5-(2-oxo-6-phenyl-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   2-ethoxy-4-(2-imino-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   (Z)-2-ethoxy-4-(2-(methylimino)-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-chloro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   6-(3-chloro-5-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;-   2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonic    acid;-   (S)-3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-fluoro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(4-hydroxy-3-nitro-5-propoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyrazin-2-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(quinolin-6-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(isoquinolin-6-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   3-ethoxy-2-hydroxy-5-(5-(3-methoxyphenyl)-2-oxo-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(4-hydroxy-3-(2-hydroxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-5-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   2-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-ethylphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   (S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   2-chloro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   (S)-3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   (S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-ethoxy-6-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one;-   3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(4-hydroxy-3-nitro-5-(trifluoromethyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(4-hydroxy-3-(2-methoxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(4-hydroxy-3-nitro-5-propylphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoic    acid;-   2-fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   2-hydroxy-4-(2-oxo-5-phenyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   2-ethoxy-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(4-(2H-tetrazol-5-yl)phenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   2-chloro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(4-(2H-tetrazol-5-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-6-methoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(4-(2H-tetrazol-5-yl)phenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   (S)-2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic    acid;-   4-(3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   6-cyclopentyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   6-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((S)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;-   4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((R)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;    and-   5-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one.

Also provided are compounds having a structure shown in Formula II, or apharmaceutically acceptable salt, stereoisomer, or prodrug thereof:

whereinX is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,heterocyclyl, and substituted heterocyclyl, each having 6 members orless in the ring;Y is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, C₄-C₆ cycloalkyl, substituted C₄-C₆cycloalkyl, heterocyclyl, and substituted heterocyclyl;Z is selected from the group consisting of O, S and NR₇;R₁, R₂ and R₇ are independently selected from the group consisting ofhydrogen, and C₁-C₆ alkyl;R₃ is selected from the group consisting of cyano, carboxy, carbamoyl,isoxazol-4-yl, and C(NH)NHOH; andR₆ is selected from the group consisting of hydrogen and hydroxy.

In a further aspect of the invention, R₁, R₂ and R₇ are independentlyselected from the group consisting of hydrogen and methyl; R₃ isselected from the group consisting of hydrogen, nitro, cyano, carboxy,carbamoyl, methylsulfonamido, fluoro, chloro, bromo, hydroxy,methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy,—C(NH)NHOH, sulfonic acid, and acetyl; and R₆ is hydrogen. In a furtheraspect of the invention, R₁, R₂ and R₇ are independently selected fromthe group consisting of hydrogen and methyl; R₃ is selected from thegroup consisting of nitro, cyano, carboxy, carbamoyl, methylsulfonamido,fluoro, chloro, bromo, hydroxy, methylsulfonyl, and methylsulfinyl,isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl andR₆ is hydrogen. In a further aspect of the invention, suitableidentities for X include, but are not limited to phenyl, substitutedphenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substitutedthiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl, andsubstituted pyridin-yl, cyclohexyl, and substituted cyclohexyl. In afurther aspect of the invention, suitable identities for X include, butare not limited to, phenyl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl,2-fluorophenyl, p-tolyl, m-tolyl, biphenyl-4-yl, 4-methoxyphenyl,3-chlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl,3,4-dimethoxyphenyl, 4-bromophenyl, o-tolyl, 4-chlorophenyl,2-chlorophenyl, 3-cyanophenyl, 3,4-difluorophenyl, 4-cyanophenyl,3-carbamoylphenyl, pyrazin-2-yl, biphenyl-3-yl, 2-cyanophenyl,pyridin-4-yl, and pyridin-3-yl, 4-(dimethylamino)phenyl, 3-fluorophenyl,3-ethylphenyl, and cyclohexyl. In a further aspect of the invention,suitable identities for Y include, but are not limited to phenyl,substituted phenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl,substituted thiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl,substituted pyridin-yl, furan-yl, substituted furan-yl,benzo[d][1,3]dioxol-yl, substituted benzo[d][1,3]dioxol-yl, imidazol-yl,substituted imidazol-yl, naphthalen-yl, substituted naphthalen-yl,pyrrol-yl, substituted pyrrol-yl, pyrazol-yl, substituted pyrazol-yl,tetrahydrofuran-yl, substituted tetrahydrofuran-yl, cyclopentyl,substituted cyclopentyl, cyclohexyl, and substituted cyclohexyl. In afurther aspect of the invention, suitable identities for Y include, butare not limited to, phenyl, 3-methoxyphenyl, p-tolyl, 4-methoxyphenyl,3,5-dichlorophenyl, 3-fluorophenyl, 4-bromophenyl, biphenyl-4-yl,4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dimethoxyphenyl,3-fluoro-4-methoxyphenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3,4-dichlorophenyl, 4-hydroxyphenyl, 2,4-difluorophenyl, furan-3-yl,2-chlorophenyl, 3-cyanophenyl, 4-(dimethylamino)phenyl, 2-fluorophenyl,4-morpholinophenyl, 4-aminophenyl, naphthal-2-yl,benzo[d][1,3]dioxol-5-yl, 4-cyanophenyl, naphthal-3-yl, naphthal-4-yl,4-acetamidophenyl, thiophen-2-yl, thiophen-3-yl,1-methyl-1H-imidazol-4-yl, naphthalene-1-yl, methyl phenylcarbamate, andnaphthalene-2-yl, 4-(methanesulfonamido)phenyl, 1H-pyrrol-3-yl,1-(phenylsulfonyl)-1H-pyrrol-3-yl, furan-2-yl,4-(trifluoromethyl)phenyl, o-tolyl, 1-methyl-1H-pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 3-chloro-5-fluorophenyl, 3-hydroxyphenyl,pyrazin-2-yl, quinolin-6-yl, isoquinolin-6-yl, 1-methyl-1H-pyrazol-5-yl,tetrahydrofuran-2-yl, cyclopentyl, tetrahydrofuran-3-yl, and cyclohexyl.

In a further aspect of the invention, suitable compounds of Formula IIinclude, but are not limited to:

-   4-(3-(isoxazol-4-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;-   3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;-   2-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;-   3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide;    and-   N-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzimidamide.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

The compounds described herein may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Alltautomers of shown or described compounds are also considered to be partof the present invention.

It is to be understood that isomers arising from such asymmetry (e.g.,all enantiomers and diastereomers) are included within the scope of theinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof. Alkenes can include either the E- or Z-geometry,where appropriate.

2. Representative Compounds

Examples 1-177 list representative novel dihydropyrimidin-2(1H)-oneanalogs of Formula I. The synthetic methods that can be used to prepareeach compound are detailed in Examples 1-177, with reference tointermediates described in Example 178. Supporting mass spectrometrydata and proton NMR data for each compound is also included in Examples1-177. Optical rotation data is included when available for enantiomerpairs.

GSNOR inhibitor activity was determined by the assay described inExample 179 and IC₅₀ values were obtained. GSNOR inhibitor compounds inExamples 1-87, 89-91, 93, 95-103, 105-170, 172-177 had an IC₅₀ of about<100 μM. GSNOR inhibitor compounds in Examples 1, 2, 4-13, 15-17, 20-23,26, 28-39, 43-61, 63, 65, 67, 69, 71, 73, 77-81, 83-86, 95, 101-102,105-116, 118-121, 125-139, 141-143, 146-148, 150-152, 154-156, 158-161,163, 165, 167, 169, 170, 172-175, and 177 had an IC₅₀ of about <1.0 μM.GSNOR inhibitor compounds in Examples 1, 2, 4-6, 9, 13, 15-17, 20-21,23, 29, 31-39, 43-51, 53, 55-57, 61, 63, 65, 67, 71, 73, 78-79, 81, 83,101-102, 107-109, 111, 113, 115-116, 118-121, 125, 129-139, 141-143,146, 148, 155-156, 158-159, 161, 163, 165, 167, 169, 172, 174, and 177had an IC₅₀ of about less than 0.1 μM.

In certain embodiments of the invention it has been demonstrated thatracemic mixtures have GSNOR inhibitor activity and in some instanceswhen the separated enantiomers are produced, one of the enantiomers hasthe majority of the GSNOR inhibitor activity and the other enantiomer issignificantly less active as a GSNOR inhibitor. For example thefollowing Table 1 shows racemates and separated enantiomers and theirIC₅₀ data. Without being bound by theory, it is believed that when theenantiomers of a GSNOR inhibitor are separated, the enantiomer whichdemonstrates significantly better GSNOR inhibitor activity is of the Sconfiguration. For example, Example 2 (the separated enantiomer ofExample 1 with significantly better activity as a GSNOR inhibitor) hasbeen shown by X-ray crystallography to have an S configuration whencrystallized with GSNOR. See Table 1 below for GSNOR IC₅₀ data(procedure for obtaining GSNOR IC₅₀ is detailed in Example 179).

TABLE 1 GSNOR Example # Configuration IC₅₀ (nM) 1 racemic 29 2 S 11 3 R19720 5 racemic 19 6 S 18 7 R 1820 65 racemic 43 67 S 28 66 R 6020 126racemic 150 125 S 67 124 R 3170 116 racemic 24 143 S 16 144 R 1900 142racemic 27 146 S 13 147 R 580 119 racemic 40 148 S 35 149 R 31000 159racemic 39 169 S 23 168 R 4250

C. Definitions

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent on the context in which it isused. If there are uses of the term which are not clear to persons ofordinary skill in the art given the context in which it is used, “about”will mean up to plus or minus 10% of the particular term.

The term “acyl” includes compounds and moieties that contain the acetylradical (CH₃CO—) or a carbonyl group to which a straight or branchedchain lower alkyl residue is attached.

The term “alkyl” as used herein refers to a straight or branched chain,saturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₆) alkyl is meant to include, but is not limited tomethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group canbe unsubstituted or optionally substituted with one or more substituentsas described herein.

The term “alkenyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one double bond. Examples of a (C₂-C₈) alkenyl group include,but are not limited to, ethylene, propylene, 1-butylene, 2-butylene,isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene,2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene,isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene. Analkenyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein.

The term “alkynyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one triple bond. Examples of a (C₂-C₈) alkynyl group include,but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne,2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. Analkynyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein.

The term “alkoxy” as used herein refers to an —O-alkyl group having theindicated number of carbon atoms. For example, a (C₁-C₆) alkoxy groupincludes —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl,—O-sec-butyl, —O-tert-butyl, —O-pentyl, —O— isopentyl, —O-neopentyl,—O-hexyl, —O-isohexyl, and —O-neohexyl.

The term “aminoalkyl” as used herein, refers to an alkyl group(typically one to six carbon atoms) wherein one or more of the C₁-C₆alkyl group's hydrogen atoms is replaced with an amine of formula—N(R^(c))₂, wherein each occurrence of R^(c) is independently —H or(C₁-C₆) alkyl. Examples of aminoalkyl groups include, but are notlimited to, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂N(CH₃)₂,t-butylaminomethyl, isopropylaminomethyl and the like.

The term “aryl” as used herein refers to a 5- to 14-membered monocyclic,bicyclic or tricyclic aromatic ring system. Examples of an aryl groupinclude phenyl and naphthyl. An aryl group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow. Examples of aryl groups include phenyl or aryl heterocycles suchas, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole,triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine,pyridazine, and pyrimidine, and the like.

As used herein, the term “bioactivity” indicates an effect on one ormore cellular or extracellular process (e.g., via binding, signaling,etc.) which can impact physiological or pathophysiological processes.

The term “carbonyl” includes compounds and moieties which contain acarbon connected with a double bond to an oxygen atom. Examples ofmoieties containing a carbonyl include, but are not limited to,aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.

The term “carboxy” or “carboxyl” means a —COOH group or carboxylic acid.

The term “C_(m)-C_(n)” means “m” number of carbon atoms to “n” number ofcarbon atoms. For example, the term “C₁-C₆” means one to six carbonatoms (C₁, C₂, C₃, C₄, C₅ or C₆). The term “C₂-C₆” includes two to sixcarbon atoms (C₂, C₃, C₄, C₅ or C₆). The term “C₃-C₆” includes three tosix carbon atoms (C₃, C₄, C₅ or C₆).

The term “cycloalkyl” as used herein refers to a 3- to 14-memberedsaturated or unsaturated non-aromatic monocyclic, bicyclic or tricyclichydrocarbon ring system. Included in this class are cycloalkyl groupswhich are fused to a benzene ring. Representative cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,-1,3,5-cyclooctatrienyl, decahydronaphthalene, octahydronaphthalene,hexahydronaphthalene, octahydroindene, hexahydroindene, tetrahydroinden,decahydrobenzocycloheptene, octahydrobenzocycloheptene,hexahydrobenzocycloheptene, tetrahydrobenzocyclopheptene,dodecahydroheptalene, decahydroheptalene, octahydroheptalene,hexahydroheptalene, and tetrahydroheptalene,(1s,3s)-bicyclo[1.1.0]butane, bicyclo[1.1.1]pentane,bicyclo[2.1.1]hexane, Bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane,bicyclo[3.3.2]decane, bicyclo[3.3.]undecane, bicyclo[4.2.2]decane,bicyclo[4.3.1]decane. A cycloalkyl group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.

The term “haloalkyl,” as used herein, refers to a C₁-C₆ alkyl groupwherein from one or more of the C₁-C₆ alkyl group's hydrogen atom isreplaced with a halogen atom, which can be the same or different.Examples of haloalkyl groups include, but are not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainalkyl, or combinations thereof, consisting of carbon atoms and from oneto three heteroatoms selected from the group consisting of O, N and S,and wherein the nitrogen and sulfur atoms may optionally be oxidized andthe nitrogen heteroatom may optionally be quaternized. The heteroatom(s)O, N and S can be placed at any position of the heteroalkyl group.Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, and—CH₂—CH═N—OCH₃. Up to two heteroatoms can be consecutive, such as, forexample, —CH₂—NH—OCH₃. When a prefix such as (C₂-C₈) is used to refer toa heteroalkyl group, the number of carbons (2 to 8, in this example) ismeant to include the heteroatoms as well. For example, a C₂-heteroalkylgroup is meant to include, for example, —CH₂OH (one carbon atom and oneheteroatom replacing a carbon atom) and —CH₂SH.

To further illustrate the definition of a heteroalkyl group, where theheteroatom is oxygen, a heteroalkyl group can be an oxyalkyl group. Forinstance, (C₂-C₅) oxyalkyl is meant to include, for example —CH₂—O—CH₃(a C₃-oxyalkyl group with two carbon atoms and one oxygen replacing acarbon atom), —CH₂CH₂CH₂CH₂OH, —OCH₂CH₂OCH₂CH₂OH, —OCH₂CH(OH)CH₂OH, andthe like.

The term “heteroaryl” as used herein refers to an aromatic heterocyclering of 5 to 14 members and having at least one heteroatom selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom,including monocyclic, bicyclic, and tricyclic ring systems.Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thienyl, benzothienyl, quinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl, quinoxalinyland oxazolyl. A heteroaryl group can be unsubstituted or optionallysubstituted with one or more substituents as described herein below.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

As used herein, the term “heterocycle” refers to 3- to 14-membered ringsystems which are either saturated, unsaturated, or aromatic, and whichcontains from 1 to 4 heteroatoms independently selected from nitrogen,oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms canbe optionally oxidized, and the nitrogen heteroatom can be optionallyquaternized, including, including monocyclic, bicyclic, and tricyclicring systems. The bicyclic and tricyclic ring systems may encompass aheterocycle or heteroaryl fused to a benzene ring. The heterocycle canbe attached via any heteroatom or carbon atom, where chemicallyacceptable. Heterocycles include heteroaryls as defined above.Representative examples of heterocycles include, but are not limited to,aziridinyl, oxiranyl, thiiranyl, triazolyl, tetrazolyl, azirinyl,diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl,oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl, tetrazinyl,imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl,pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl,benzthiazolyl, thienyl, pyrazolyl, triazolyl, pyrimidinyl,benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl,quinolinyl and quinazolinyl. A heterocycle group can be unsubstituted oroptionally substituted with one or more substituents as described hereinbelow.

The term “heterocycloalkyl,” by itself or in combination with otherterms, represents, unless otherwise stated, cyclic versions of“heteroalkyl.” Additionally, a heteroatom can occupy the position atwhich the heterocycle is attached to the remainder of the molecule.Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl),1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, and the like.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group havingthe indicated number of carbon atoms wherein one or more of the hydrogenatoms in the alkyl group is replaced with an —OH group. Examples ofhydroxyalkyl groups include, but are not limited to, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂CH₂CH₂OH, and branched versions thereof.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

As used herein and unless otherwise indicated, the term “stereoisomer”means one stereoisomer of a compound that is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecompound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. In some embodiments, a stereomericallypure compound comprises greater than about 80% by weight of onestereoisomer of the compound and less than about 20% by weight of otherstereoisomers of the compound, for example greater than about 90% byweight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein, “protein” is used synonymously with “peptide,”“polypeptide,” or “peptide fragment”. A “purified” polypeptide, protein,peptide, or peptide fragment is substantially free of cellular materialor other contaminating proteins from the cell, tissue, or cell-freesource from which the amino acid sequence is obtained, or substantiallyfree from chemical precursors or other chemicals when chemicallysynthesized.

As used herein, “modulate” is meant to refer to an increase or decreasein the levels of a peptide or a polypeptide, or to increase or decreasethe stability or activity of a peptide or a polypeptide. The term“inhibit” is meant to refer to a decrease in the levels of a peptide ora polypeptide or to decrease in the stability or activity of a peptideor a polypeptide. In preferred embodiments, the peptide which ismodulated or inhibited is S-nitrosoglutathione (GSNO) or proteinS-nitrosothiols (SNOs).

As used here, the terms “nitric oxide” and “NO” encompass unchargednitric oxide and charged nitric oxide species, particularly includingnitrosonium ion (NO⁺) and nitroxyl ion (NO⁻). The reactive form ofnitric oxide can be provided by gaseous nitric oxide. Compounds havingthe structure X—NO_(y) wherein X is a nitric oxide releasing, deliveringor transferring moiety, including any and all such compounds whichprovide nitric oxide to its intended site of action in a form active fortheir intended purpose, and Y is 1 or 2.

As utilized herein, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of a federal or a state government orlisted in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals and, more particularly, in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich the therapeutic is administered and includes, but is not limitedto such sterile liquids as water and oils.

A “pharmaceutically acceptable salt” or “salt” of a compound of theinvention is a product of the disclosed compound that contains an ionicbond, and is typically produced by reacting the disclosed compound witheither an acid or a base, suitable for administering to a subject. Apharmaceutically acceptable salt can include, but is not limited to,acid addition salts including hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates,succinates, lactates, and tartrates; alkali metal cations such as Li,Na, K, alkali earth metal salts such as Mg or Ca, or organic aminesalts.

A “pharmaceutical composition” is a formulation comprising the disclosedcompounds in a form suitable for administration to a subject. Apharmaceutical composition of the invention is preferably formulated tobe compatible with its intended route of administration. Examples ofroutes of administration include, but are not limited to, oral andparenteral, e.g., intravenous, intradermal, subcutaneous, inhalation,topical, transdermal, transmucosal, and rectal administration.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Substituents for the groups referred to as alkyl, heteroalkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl can be selected from a variety of groups including—OR^(d)′, ═O, ═NR^(d)′, ═N—OR^(d)′, —NR^(d)′R^(d)″, SR^(d)′, -halo,—SiR^(d)′R^(d)″R^(d)′″, —OC(O)R^(d)′, —C(O)R^(d)′, —CO₂R^(d)′,—CONR^(d)′R^(d)″, —OC(O)NR^(d)′R^(d)″, —NR^(d)″C(O)R^(d)′,—NR^(d)′″C(O)NR^(d)′R^(d)″, —NR^(d)′″SO₂NR^(d)′R^(d)″,—NR^(d)″CO₂R^(d)′, —NHC(NH₂)═NH, —NR^(a)′C(NH₂)═NH, —NHC(NH₂)═NR^(d)′,—S(O)R^(d)′, —SO₂R^(d)′, —SO₂NR^(d)′R^(d)″, —NR^(d)″SO₂R^(d)′, —CN and—NO₂, in a number ranging from zero to three, with those groups havingzero, one or two substituents being exemplary.

R^(d)′, R^(d)″ and R^(d)′″ each independently refer to hydrogen,unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈) alkyl,unsubstituted aryl and aryl substituted with one to three substituentsselected from -halo, unsubstituted alkyl, unsubstituted alkoxy,unsubstituted thioalkoxy and unsubstituted aryl (C₁-C₄)alkyl. WhenR^(d)′ and R^(d)″ are attached to the same nitrogen atom, they can becombined with the nitrogen atom to form a 5-, 6- or 7-membered ring. Forexample, —NR^(d)′R^(d)″ can represent 1-pyrrolidinyl or 4-morpholinyl.

Typically, an alkyl or heteroalkyl group will have from zero to threesubstituents, with those groups having two or fewer substituents beingexemplary of the present invention. An alkyl or heteroalkyl radical canbe unsubstituted or monosubstituted. In some embodiments, an alkyl orheteroalkyl radical will be unsubstituted.

Exemplary substituents for the alkyl and heteroalkyl radicals includebut are not limited to —OR^(d)′, ═O, ═NR^(d)′, ═N—OR^(d)′,—NR^(d)′R^(d)″, —SR^(d)′, -halo, —SiR^(d)′R^(d)″R^(d)′″, —OC(O)R^(d)′,—C(O)R^(d)′, —CO₂R^(d)′, —CONR^(d)′R^(d)″, —OC(O)NR^(d)′R^(d)″,—NR^(d)″C(O)R^(d)′, —NR^(d)′″C(O)NR^(d)′R^(d)″,—NR^(d)′″SO₂NR^(d)′R^(d)″, —NR^(d)″CO₂R^(d)′, —NHC(NH₂)═NH,—NR^(a)′C(NH₂)═NH, —NHC(NH₂)═NR^(d)′, —S(O)R^(d)′, —SO₂R^(d)′,—SO₂NR^(d)′R^(d)″, —NR^(d)″SO₂R^(d)′, —CN and —NO₂, where R^(d)′, R^(d)″and R^(d)′″ are as defined above. Typical substituents can be selectedfrom: —OR″, ═O, —NR^(d)′R^(d)″, -halo, —OC(O)R^(d)′, —CO₂R^(d)′,—C(O)NR^(d)′R^(d)″, —OC(O)NR^(d)′R^(d)″, —NR^(d)″C(O)R^(d)′,—NR^(d)″CO₂R^(d)′, —NR^(d)′″SO₂NR^(d)′R^(d)″, —SO₂R^(d)′,—SO₂NR^(d)′R^(d)″, —NR^(d)″SO₂R^(d)′-CN and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand selected from: -halo, —OR′, —OC(O)R^(e)′, —NR′R^(e)″, —SR′, —R^(e)′,—CN, —NO₂, —CO₂R^(e)′, —C(O)NR′R^(e)″, —C(O)R^(e)′, —OC(O)NR′R^(e)″,—NR^(e)″C(O)R^(e)′, —NR^(e)″CO₂R^(e)′, —NR′″C(O)NR′R^(e)″,—NR^(e)′SO₂NR^(e)′R^(e)″, —NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—S(O)R^(e)′, —SO₂R^(e)′, —SO₂NR′R^(e)″, —NR^(e)″SO₂R′, —N₃, —CH(Ph)₂,perfluoroalkoxy and perfluoro(C₁-C₄)alkyl, in a number ranging from zeroto the total number of open valences on the aromatic ring system.

R^(e)′, R^(e)″ and R^(e)′″ are independently selected from hydrogen,unsubstituted (C₁-C₈) alkyl, unsubstituted hetero(C₁-C₈) alkyl,unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aryl(C₁-C₄)alkyl and unsubstituted aryloxy(C₁-C₄) alkyl. Typically, an aryl orheteroaryl group will have from zero to three substituents, with thosegroups having two or fewer substituents being exemplary in the presentinvention. In one embodiment of the invention, an aryl or heteroarylgroup will be unsubstituted or monosubstituted. In another embodiment,an aryl or heteroaryl group will be unsubstituted.

Two of the substituents on adjacent atoms of an aryl or heteroaryl ringin an aryl or heteroaryl group as described herein may optionally bereplaced with a substituent of the formula -T-C(O)—(CH₂)_(q)—U—, whereinT and U are independently —NH—, —O—, —CH₂— or a single bond, and q is aninteger of from 0 to 2. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -J-(CH₂)_(r)—K—, wherein J and K areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR^(f)′- ora single bond, and r is an integer of from 1 to 3. One of the singlebonds of the new ring so formed may optionally be replaced with a doublebond. Alternatively, two of the substituents on adjacent atoms of thearyl or heteroaryl ring may optionally be replaced with a substituent ofthe formula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR^(f)′—, —S—, —S(O)—, —S(O)₂—,or —S(O)₂NR^(a)′—. The substituent R^(f)′ in —NR^(f)′— and—S(O)₂NR^(f)′— is selected from hydrogen or unsubstituted (C₁-C₆) alkyl.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein the term “therapeutically effective amount” generallymeans the amount necessary to ameliorate at least one symptom of adisorder to be prevented, reduced, or treated as described herein. Thephrase “therapeutically effective amount” as it relates to the GSNORinhibitors of the present invention shall mean the GSNOR inhibitordosage that provides the specific pharmacological response for which theGSNOR inhibitor is administered in a significant number of subjects inneed of such treatment. It is emphasized that a therapeuticallyeffective amount of a GSNOR inhibitor that is administered to aparticular subject in a particular instance will not always be effectivein treating the conditions/diseases described herein, even though suchdosage is deemed to be a therapeutically effective amount by those ofskill in the art.

The term “biological sample” includes, but is not limited to, samples ofblood (e.g., serum, plasma, or whole blood), urine, saliva, sweat,breast milk, vaginal secretions, semen, hair follicles, skin, teeth,bones, nails, or other secretions, body fluids, tissues, or cells. Inaccordance with the invention, the levels of the S-nitrosoglutathionereductase in the biological sample can be determined by the methodsdescribed in U.S. Patent Application Publication No. 2005/0014697.

D. Pharmaceutical Compositions

The invention encompasses pharmaceutical compositions comprising atleast one compound of the invention described herein and at least onepharmaceutically acceptable carrier. Suitable carriers are described in“Remington: The Science and Practice, Twentieth Edition,” published byLippincott Williams & Wilkins, which is incorporated herein byreference. Pharmaceutical compositions according to the invention mayalso comprise one or more non-inventive compound active agents.

The pharmaceutical compositions of the invention can comprise novelcompounds described herein, the pharmaceutical compositions can compriseknown compounds which previously were not known to have GSNOR inhibitoractivity, or a combination thereof.

The compounds of the invention can be utilized in any pharmaceuticallyacceptable dosage form, including but not limited to injectable dosageforms, liquid dispersions, gels, aerosols, ointments, creams,lyophilized formulations, dry powders, tablets, capsules, controlledrelease formulations, fast melt formulations, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, mixed immediate release and controlled releaseformulations, etc. Specifically, the compounds of the inventiondescribed herein can be formulated: (a) for administration selected fromthe group consisting of oral, pulmonary, intravenous, intra-arterial,intrathecal, intra-articular, rectal, ophthalmic, colonic, parenteral,intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, andtopical administration; (b) into a dosage form selected from the groupconsisting of liquid dispersions, gels, aerosols, ointments, creams,tablets, sachets and capsules; (c) into a dosage form selected from thegroup consisting of lyophilized formulations, dry powders, fast meltformulations, controlled release formulations, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, and mixed immediate release and controlled releaseformulations; or (d) any combination thereof.

For respiratory infections, an inhalation formulation can be used toachieve high local concentrations. Formulations suitable for inhalationinclude dry power or aerosolized or vaporized solutions, dispersions, orsuspensions capable of being dispensed by an inhaler or nebulizer intothe endobronchial or nasal cavity of infected patients to treat upperand lower respiratory bacterial infections.

Solutions or suspensions used for parenteral, intradermal, orsubcutaneous application can comprise one or more of the followingcomponents: (1) a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; (2) antibacterial agents such as benzylalcohol or methyl parabens; (3) antioxidants such as ascorbic acid orsodium bisulfite; (4) chelating agents such asethylenediaminetetraacetic acid; (5) buffers such as acetates, citratesor phosphates; and (5) agents for the adjustment of tonicity such assodium chloride or dextrose. The pH can be adjusted with acids or bases,such as hydrochloric acid or sodium hydroxide. A parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

Pharmaceutical compositions suitable for injectable use may comprisesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. The pharmaceutical composition should bestable under the conditions of manufacture and storage and should bepreserved against the contaminating action of microorganisms such asbacteria and fungi.

The carrier can be a solvent or dispersion medium comprising, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), and suitablemixtures thereof. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms can be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol or sorbitol, and inorganic saltssuch as sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activereagent in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating at least one compound of the invention into a sterilevehicle that contains a basic dispersion medium and any other requiredingredients. In the case of sterile powders for the preparation ofsterile injectable solutions, exemplary methods of preparation includevacuum drying and freeze-drying, both of which yield a powder of acompound of the invention plus any additional desired ingredient from apreviously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed, for example, in gelatin capsules orcompressed into tablets. For the purpose of oral therapeuticadministration, the compound of the invention can be incorporated withexcipients and used in the form of tablets, troches, or capsules. Oralcompositions can also be prepared using a fluid carrier for use as amouthwash, wherein the compound in the fluid carrier is applied orallyand swished and expectorated or swallowed. Pharmaceutically compatiblebinding agents, and/or adjuvant materials can be included as part of thecomposition.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser thatcontains a suitable propellant, e.g., a gas such as carbon dioxide, anebulized liquid, or a dry powder from a suitable device. Fortransmucosal or transdermal administration, penetrants appropriate tothe barrier to be permeated are used in the formulation. Such penetrantsare generally known in the art, and include, for example, fortransmucosal administration, detergents, bile salts, and fusidic acidderivatives. Transmucosal administration can be accomplished through theuse of nasal sprays or suppositories. For transdermal administration,the active reagents are formulated into ointments, salves, gels, orcreams as generally known in the art. The reagents can also be preparedin the form of suppositories (e.g., with conventional suppository basessuch as cocoa butter and other glycerides) or retention enemas forrectal delivery.

In one embodiment, the compounds of the invention are prepared withcarriers that will protect against rapid elimination from the body. Forexample, a controlled release formulation can be used, includingimplants and microencapsulated delivery systems. Biodegradable,biocompatible polymers can be used, such as ethylene vinyl acetate,polyanhydrides, polyglycolic acid, collagen, polyorthoesters, andpolylactic acid. Methods for preparation of such formulations will beapparent to those skilled in the art.

Liposomal suspensions (including liposomes targeted to infected cellswith monoclonal antibodies to viral antigens) can also be used aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811.

Additionally, suspensions of the compounds of the invention may beprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles include fatty oils, such as sesame oil, orsynthetic fatty acid esters, such as ethyl oleate, triglycerides, orliposomes. Non-lipid polycationic amino polymers may also be used fordelivery. Optionally, the suspension may also include suitablestabilizers or agents to increase the solubility of the compounds andallow for the preparation of highly concentrated solutions.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of thecompound of the invention calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Thespecification for the dosage unit forms of the invention are dictated byand directly dependent on the unique characteristics of the compound ofthe invention and the particular therapeutic effect to be achieved, andthe limitations inherent in the art of compounding such an active agentfor the treatment of individuals.

Pharmaceutical compositions according to the invention comprising atleast one compound of the invention can comprise one or morepharmaceutical excipients. Examples of such excipients include, but arenot limited to binding agents, filling agents, lubricating agents,suspending agents, sweeteners, flavoring agents, preservatives, buffers,wetting agents, disintegrants, effervescent agents, and otherexcipients. Such excipients are known in the art. Exemplary excipientsinclude: (1) binding agents which include various celluloses andcross-linked polyvinylpyrrolidone, microcrystalline cellulose, such asAvicel® PH101 and Avicel® PH102, silicified microcrystalline cellulose(ProSolv SMCC™), gum tragacanth and gelatin; (2) filling agents such asvarious starches, lactose, lactose monohydrate, and lactose anhydrous;(3) disintegrating agents such as alginic acid, Primogel, corn starch,lightly crosslinked polyvinyl pyrrolidone, potato starch, maize starch,and modified starches, croscarmellose sodium, cross-povidone, sodiumstarch glycolate, and mixtures thereof; (4) lubricants, including agentsthat act on the flowability of a powder to be compressed, includemagnesium stearate, colloidal silicon dioxide, such as Aerosil® 200,talc, stearic acid, calcium stearate, and silica gel; (5) glidants suchas colloidal silicon dioxide; (6) preservatives, such as potassiumsorbate, methylparaben, propylparaben, benzoic acid and its salts, otheresters of parahydroxybenzoic acid such as butylparaben, alcohols such asethyl or benzyl alcohol, phenolic compounds such as phenol, orquaternary compounds such as benzalkonium chloride; (7) diluents such aspharmaceutically acceptable inert fillers, such as microcrystallinecellulose, lactose, dibasic calcium phosphate, saccharides, and/ormixtures of any of the foregoing; examples of diluents includemicrocrystalline cellulose, such as Avicel® PH101 and Avicel® PH102;lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose®DCL21; dibasic calcium phosphate such as Emcompress; mannitol; starch;sorbitol; sucrose; and glucose; (8) sweetening agents, including anynatural or artificial sweetener, such as sucrose, saccharin sucrose,xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame; (9)flavoring agents, such as peppermint, methyl salicylate, orangeflavoring, Magnasweet® (trademark of MAFCO), bubble gum flavor, fruitflavors, and the like; and (10) effervescent agents, includingeffervescent couples such as an organic acid and a carbonate orbicarbonate. Suitable organic acids include, for example, citric,tartaric, malic, fumaric, adipic, succinic, and alginic acids andanhydrides and acid salts. Suitable carbonates and bicarbonates include,for example, sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, magnesium carbonate, sodium glycine carbonate,L-lysine carbonate, and arginine carbonate. Alternatively, only thesodium bicarbonate component of the effervescent couple may be present.

E. Kits Comprising the Compositions of the Invention

The present invention also encompasses kits comprising the compositionsof the invention. Such kits can comprise, for example, (1) at least onecompound of the invention; and (2) at least one pharmaceuticallyacceptable carrier, such as a solvent or solution. Additional kitcomponents can optionally include, for example: (1) any of thepharmaceutically acceptable excipients identified herein, such asstabilizers, buffers, etc., (2) at least one container, vial or similarapparatus for holding and/or mixing the kit components; and (3) deliveryapparatus, such as an inhaler, nebulizer, syringe, etc.

F. Methods of Preparing Compounds of the Invention

The compounds of the invention can readily be synthesized using knownsynthetic methodologies or via a modification of known syntheticmethodologies. As would be readily recognized by a skilled artisan, themethodologies described below allow the synthesis ofdihydropyrimidin-2(1H)-ones having a variety of substituents. Exemplarysynthetic methods are described in the examples below.

If needed, further purification and separation of enantiomers anddiastereomers can be achieved by routine procedures known in the art.Thus, for example, the separation of enantiomers of a compound can beachieved by the use of chiral HPLC and related chromatographictechniques. Diastereomers can be similarly separated. In some instances,however, diastereomers can simply be separated physically, such as, forexample, by controlled precipitation or crystallization.

The process of the invention, when carried out as prescribed herein, canbe conveniently performed at temperatures that are routinely accessiblein the art. In one embodiment, the process is performed at a temperaturein the range of about 25° C. to about 110° C. In another embodiment, thetemperature is in the range of about 40° C. to about 100° C. In yetanother embodiment, the temperature is in the range of about 50° C. toabout 95° C.

Synthetic steps that require a base are carried out using any convenientorganic or inorganic base. Typically, the base is not nucleophilic.Thus, in one embodiment, the base is selected from carbonates,phosphates, hydroxides, alkoxides, salts of disilazanes, and tertiaryamines.

The process of the invention, when performed as described herein, can besubstantially complete after several minutes to after several hoursdepending upon the nature and quantity of reactants and reactiontemperature. The determination of when the reaction is substantiallycomplete can be conveniently evaluated by ordinary techniques known inthe art such as, for example, HPLC, LCMS, TLC, and ¹H NMR.

G. Methods of Treatment

The invention encompasses methods of preventing or treating (e.g.,alleviating one or more symptoms of) medical conditions through use ofone or more of the disclosed compounds. The methods compriseadministering a therapeutically effective amount of a compound of theinvention to a patient in need. The compositions of the invention canalso be used for prophylactic therapy.

The compound of the invention used in the methods of treatment accordingto the invention can be: (1) a novel compound described herein, or apharmaceutically acceptable salt thereof, a prodrug thereof, or ametabolite thereof; (2) a compound which was known prior to the presentinvention, but wherein it was not known that the compound is a GSNORinhibitor, or a pharmaceutically acceptable salt thereof, a prodrugthereof, or a metabolite thereof; or (3) a compound which was knownprior to the present invention, and wherein it was known that thecompound is a GSNOR inhibitor, but wherein it was not known that thecompound is useful for the methods of treatment described herein, or apharmaceutically acceptable salt thereof, a prodrug thereof, or ametabolite thereof.

The patient can be any animal, domestic, livestock or wild, including,but not limited to cats, dogs, horses, pigs and cattle, and preferablyhuman patients. As used herein, the terms patient and subject may beused interchangeably.

As used herein, “treating” describes the management and care of apatient for the purpose of combating a disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, alleviating thesymptoms or complications, or eliminating the disease, condition ordisorder. More specifically, “treating” includes reversing, attenuating,alleviating, minimizing, suppressing or halting at least one deleterioussymptom or effect of a disease (disorder) state, disease progression,disease causative agent (e.g., bacteria or viruses), or other abnormalcondition. Treatment is continued as long as symptoms and/or pathologyameliorate.

In general, the dosage, i.e., the therapeutically effective amount,ranges from 1 μg to 10 g/kg and often ranges from 10 μg to 1 g/kg or 10μg to 100 mg/kg body weight of the subject being treated, per day.

H. GSNOR Uses

In subjects with deleteriously high levels of GSNOR or GSNOR activity,modulation may be achieved, for example, by administering one or more ofthe disclosed compounds that disrupts or down-regulates GSNOR function,or decreases GSNOR levels. These compounds may be administered withother GSNOR inhibitor agents, such as anti-GSNOR antibodies or antibodyfragments, GSNOR antisense, iRNA, or small molecules, or otherinhibitors, alone or in combination with other agents as described indetail herein.

The present invention provides a method of treating a subject afflictedwith a disorder ameliorated by NO donor therapy. Such a method comprisesadministering to a subject a therapeutically effective amount of a GSNORinhibitor.

The disorders can include pulmonary disorders associated with hypoxemiaand/or smooth muscle constriction in the lungs and airways and/or lunginfection and/or lung inflammation and/or lung injury (e.g., pulmonaryhypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitiallung diseases, cystic fibrosis, COPD); cardiovascular disease and heartdisease (e.g., hypertension, ischemic coronary syndromes,atherosclerosis, heart failure, glaucoma); diseases characterized byangiogenesis (e.g., coronary artery disease); disorders where there isrisk of thrombosis occurring; disorders where there is risk ofrestenosis occurring; inflammatory diseases (e.g., AIDS relateddementia, inflammatory bowel disease (IBD), Crohn's disease, andpsoriasis); functional bowel disorders (e.g., irritable bowel syndrome(IBS)); diseases where there is risk of apoptosis occurring (e.g., heartfailure, atherosclerosis, degenerative neurologic disorders, arthritisand liver injury (ischemic or alcoholic)); impotence; sleep apnea;diabetic wound healing; cutaneous infections; treatment of psoriasis;obesity caused by eating in response to craving for food; stroke;reperfusion injury (e.g., traumatic muscle injury in heart or lung orcrush injury); and disorders where preconditioning of heart or brain forNO protection against subsequent ischemic events is beneficial, centralnervous system (CNS) disorders (e.g., anxiety, depression, psychosis,and schizophrenia); and infections caused by bacteria (e.g.,tuberculosis, c. difficile infections, among others).

In one embodiment, the compounds of the present invention or apharmaceutically acceptable salt thereof, or a prodrug or metabolitethereof, can be administered in combination with an NO donor. An NOdonor donates nitric oxide or a related redox species and more generallyprovides nitric oxide bioactivity, that is activity which is identifiedwith nitric oxide, e.g., vasorelaxation or stimulation or inhibition ofa receptor protein, e.g., ras protein, adrenergic receptor, NFκB. NOdonors including S-nitroso, O-nitroso, C-nitroso and N-nitroso compoundsand nitro derivatives thereof and metal NO complexes, but not excludingother NO bioactivity generating compounds, useful herein are describedin “Methods in Nitric Oxide Research,” Feelisch et al. eds., pages71-115 (J. S., John Wiley & Sons, New York, 1996), which is incorporatedherein by reference. NO donors which are C-nitroso compounds wherenitroso is attached to a tertiary carbon which are useful herein includethose described in U.S. Pat. No. 6,359,182 and in WO 02/34705. Examplesof S-nitroso compounds, including S-nitrosothiols useful herein,include, for example, S-nitrosoglutathione,S-nitroso-N-acetylpenicillamine, S-nitroso-cysteine and ethyl esterthereof, S-nitroso cysteinyl glycine,S-nitroso-gamma-methyl-L-homocysteine, S-nitroso-L-homocysteine,S-nitroso-gamma-thio-L-leucine, S-nitroso-delta-thio-L-leucine, andS-nitrosoalbumin. Examples of other NO donors useful herein are sodiumnitroprusside (nipride), ethyl nitrite, isosorbide, nitroglycerin, SIN 1which is molsidomine, furoxamines, N-hydroxy (N-nitrosamine) andperfluorocarbons that have been saturated with NO or a hydrophobic NOdonor.

The combination of a GSNOR inhibitor with R(+) enantiomer of amlodipine,a known NO releaser (Zhang X. P at al. 2002 J. CardiovascularPharmacology 39, 208-214) is also an embodiment of the presentinvention.

The present invention also provides a method of treating a subjectafflicted with pathologically proliferating cells where the methodcomprises administering to said subject a therapeutically effectiveamount of an inhibitor of GSNOR. The inhibitors of GSNOR are thecompounds as defined above, or a pharmaceutically acceptable saltthereof, or a prodrug or metabolite thereof, in combination with apharmaceutically acceptable carrier. Treatment is continued as long assymptoms and/or pathology ameliorate.

In another embodiment, the pathologically proliferating cells can bepathologically proliferating microbes. The microbes involved can bethose where GSNOR is expressed to protect the microbe from nitrosativestress or where a host cell infected with the microbe expresses theenzyme, thereby protecting the microbe from nitrosative stress. The term“pathologically proliferating microbes” is used herein to meanpathologic microorganisms including but not limited to pathologicbacteria, pathologic viruses, pathologic Chlamydia, pathologic protozoa,pathologic Rickettsia, pathologic fungi, and pathologic mycoplasmata.More detail on the applicable microbes is set forth at columns 11 and 12of U.S. Pat. No. 6,057,367. The term “host cells infected withpathologic microbes” includes not only mammalian cells infected withpathologic viruses but also mammalian cells containing intracellularbacteria or protozoa, e.g., macrophages containing Mycobacteriumtuberculosis, Mycobacterium leper (leprosy), or Salmonella typhi(typhoid fever).

In another embodiment, the pathologically proliferating cells can bepathologic helminths. The term “pathologic helminths” is used herein torefer to pathologic nematodes, pathologic trematodes and pathologiccestodes. More detail on the applicable helminths is set forth at column12 of U.S. Pat. No. 6,057,367.

In another embodiment, the pathologically proliferating cells can bepathologically proliferating mammalian cells. The term “pathologicallyproliferating mammalian cells” as used herein means cells of the mammalthat grow in size or number in said mammal so as to cause a deleteriouseffect in the mammal or its organs. The term includes, for example, thepathologically proliferating or enlarging cells causing restenosis, thepathologically proliferating or enlarging cells causing benign prostatichypertrophy, the pathologically proliferating cells causing myocardialhypertrophy and proliferating cells at inflammatory sites such assynovial cells in arthritis or cells associated with a cellproliferation disorder.

As used herein, the term “cell proliferative disorder” refers toconditions in which the unregulated and/or abnormal growth of cells canlead to the development of an unwanted condition or disease, which canbe cancerous or non-cancerous, for example a psoriatic condition. Asused herein, the term “psoriatic condition” refers to disordersinvolving keratinocyte hyperproliferation, inflammatory cellinfiltration, and cytokine alteration. The cell proliferative disordercan be a precancerous condition or cancer. The cancer can be primarycancer or metastatic cancer, or both.

As used herein, the term “cancer” includes solid tumors, such as lung,breast, colon, ovarian, pancreas, prostate, adenocarcinoma, squamouscarcinoma, sarcoma, malignant glioma, leiomyosarcoma, hepatoma, head andneck cancer, malignant melanoma, non-melanoma skin cancers, as well ashematologic tumors and/or malignancies, such as leukemia, childhoodleukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomasof lymphocytic and cutaneous origin, acute and chronic leukemia such asacute lymphoblastic, acute myelocytic or chronic myelocytic leukemia,plasma cell neoplasm, lymphoid neoplasm and cancers associated withAIDS.

In addition to psoriatic conditions, the types of proliferative diseaseswhich may be treated using the compositions of the present invention areepidermic and dermoid cysts, lipomas, adenomas, capillary and cutaneoushemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas,myofibromatosis, osteoplastic tumors, and other dysplastic masses andthe like. In one embodiment, proliferative diseases include dysplasiasand disorders of the like.

In one embodiment, the treating cancer comprises a reduction in tumorsize, decrease in tumor number, a delay of tumor growth, decrease inmetastaic lesions in other tissues or organs distant from the primarytumor site, an improvement in the survival of patients, or animprovement in the quality of patient life, or at least two of theabove.

In another embodiment, the treating a cell proliferative disordercomprises a reduction in the rate of cellular proliferation, reductionin the proportion of proliferating cells, a decrease in size of an areaor zone of cellular proliferation, or a decrease in the number orproportion of cells having an abnormal appearance or morphology, or atleast two of the above.

In yet another embodiment, the compounds of the present invention or apharmaceutically acceptable salt thereof, a prodrug thereof, ormetabolite thereof, can be administered in combination with a secondchemotherapeutic agent. In a further embodiment, the secondchemotherapeutic agent is selected from the group consisting oftamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin,carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine,gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin,vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone,navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone,amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib,erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab,cetuximab, and bevacizumab.

In one embodiment, the compounds of the present invention or apharmaceutically acceptable salt thereof, a prodrug thereof, ormetabolite thereof, can be administered in combination with an agentthat imposes nitrosative or oxidative stress. Agents for selectivelyimposing nitrosative stress to inhibit proliferation of pathologicallyproliferating cells in combination therapy with GSNOR inhibitors hereinand dosages and routes of administration therefor include thosedisclosed in U.S. Pat. No. 6,057,367, which is incorporated herein.Supplemental agents for imposing oxidative stress (i.e., agents thatincrease GSSG (oxidized glutathione) over GSH (glutathione) ratio orNAD(P) over NAD(P)H ratio or increase thiobarbituric acid derivatives)in combination therapy with GS-FDH inhibitors herein include, forexample, L-buthionine-S-sulfoximine (BSO), glutathione reductaseinhibitors (e.g., BCNU), inhibitors or uncouplers of mitochondrialrespiration and drugs that increase reactive oxygen species (ROS), e.g.,adriamycin, in standard dosages with standard routes of administration.

GSNOR inhibitors may also be co-administered with a phosphodiesteraseinhibitor (e.g., rolipram, cilomilast, roflumilast, Viagra® (sildenifilcitrate), Cialis® (tadalafil), Levitra® (vardenifil), etc.), aβ-agonist, a steroid, or a leukotriene antagonist (LTD-4). Those skilledin the art can readily determine the appropriate therapeuticallyeffective amount depending on the disorder to be ameliorated.

GSNOR inhibitors may be used as a means to improve β-adrenergicsignaling. In particular, inhibitors of GSNOR alone or in combinationwith β-agonists could be used to treat or protect against heart failure,or other vascular disorders such as hypertension and asthma. GSNORinhibitors can also be used to modulate G protein coupled receptors(GPCRs) by potentiating Gs G-protein, leading to smooth musclerelaxation (e.g., airway and blood vessels), and by attenuating GqG-protein, and thereby preventing smooth muscle contraction (e.g., inairway and blood vessels).

The therapeutically effective amount for the treatment of a subjectafflicted with a disorder ameliorated by NO donor therapy is the GSNORinhibiting amount in vivo that causes amelioration of the disorder beingtreated or protects against a risk associated with the disorder. Forexample, for asthma, a therapeutically effective amount is abronchodilating effective amount; for cystic fibrosis, a therapeuticallyeffective amount is an airway obstruction ameliorating effective amount;for ARDS, a therapeutically effective amount is a hypoxemia amelioratingeffective amount; for heart disease, a therapeutically effective amountis an angina relieving or angiogenesis inducing effective amount; forhypertension, a therapeutically effective amount is a blood pressurereducing effective amount; for ischemic coronary disorders, atherapeutic amount is a blood flow increasing effective amount; foratherosclerosis, a therapeutically effective amount is an endothelialdysfunction reversing effective amount; for glaucoma, a therapeuticamount is an intraocular pressure reducing effective amount; fordiseases characterized by angiogenesis, a therapeutically effectiveamount is an angiogenesis inhibiting effective amount; for disorderswhere there is risk of thrombosis occurring, a therapeutically effectiveamount is a thrombosis preventing effective amount; for disorders wherethere is risk of restenosis occurring, a therapeutically effectiveamount is a restenosis inhibiting effective amount; for chronicinflammatory diseases, a therapeutically effective amount is aninflammation reducing effective amount; for disorders where there isrisk of apoptosis occurring, a therapeutically effective amount is anapoptosis preventing effective amount; for impotence, a therapeuticallyeffective is an erection attaining or sustaining effective amount; forobesity, a therapeutically effective amount is a satiety causingeffective amount; for stroke, a therapeutically effective amount is ablood flow increasing or a TIA protecting effective amount; forreperfusion injury, a therapeutically effective amount is a functionincreasing effective amount; and for preconditioning of heart and brain,a therapeutically effective amount is a cell protective effectiveamount, e.g., as measured by triponin or CPK.

The therapeutically effective amount for the treatment of a subjectafflicted with pathologically proliferating cells means a GSNORinhibiting amount in vivo which is an antiproliferative effectiveamount. Such antiproliferative effective amount as used herein means anamount causing reduction in rate of proliferation of at least about 20%,at least about 10%, at least about 5%, or at least about 1%.

I. Uses in an Apparatus

The compounds of the present invention or a pharmaceutically acceptablesalt thereof, or a prodrug or metabolite thereof, can be applied tovarious apparatus in circumstances when the presence of such compoundswould be beneficial. Such apparatus can be any device or container, forexample, implantable devices in which a compound of the invention can beused to coat a surgical mesh or cardiovascular stent prior toimplantation in a patient. The compounds of the invention can also beapplied to various apparatus for in vitro assay purposes or forculturing cells.

The compounds of the present invention or a pharmaceutically acceptablesalt thereof, or a prodrug or metabolite thereof, can also be used as anagent for the development, isolation or purification of binding partnersto compounds of the invention, such as antibodies, natural ligands, andthe like. Those skilled in the art can readily determine related usesfor the compounds of the present invention.

EXAMPLES

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all references to a publiclyavailable document, including a U.S. patent, are specificallyincorporated by reference.

Examples 1-177 list representative novel dihydropyrimidin-2(1H)-oneanalogs of Formula I useful as GSNOR inhibitors of the invention. Thesynthetic methods that can be used to prepare each compound are detailedin Examples 1-177. Corresponding Intermediates are detailed in Example178.

A general scheme for preparing dihydropyrimidin-2(1H)-one analogs isshown here.

The di-cyclic ethanone (A) is combined with the aldehyde (B) and theurea (or thiourea or guanidine) (C), in EtOH with concentrated HCl. Thereaction is refluxed for 1-5 days. Typically the crude is purified bycolumn chromatography (silica gel) or reverse phase prep HPLC to givethe desired dihydropyrimidin-2(1H)-one compound (D). In some cases, thedi-cyclic ethanone or the aldehyde is not commercially available. Inthese cases, the synthesis of the intermediates is described in Example178. Supporting mass spectrometry data and proton NMR data for eachcompound is also included in Examples 1-177. Optical rotation data isincluded when available for enantiomer pairs.

Example 1 Compound 1,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of compound 1,2-diphenylethanone (557 mg, 2.8 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (500 mg, 2.4 mmol), and urea (427mg, 7.1 mmol) in EtOH (50 mL) was added concentrated HCl (0.24 mL), andthe reaction mixture was heated at reflux for three days. TLC(EtOAc:MeOH=10:1) showed that the starting materials were consumed. Thereaction mixture was concentrated and purified by column chromatography(EtOAc:MeOH=30:1) to afford Compound 1 as a yellow solid (500 mg, yield:49.0%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.25 (s, 1H), 8.70 (s, 1H), 7.50(s, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.15-7.25 (m, 6H), 6.95-7.05 (m, 3H),6.80 (d, J=6.4 Hz, 2H), 5.15 (d, J=2.8 Hz, 1H), 4.05 (m, 2H), 1.30 (t,J=6.8 Hz, 3H); MS (ESI): m/z 432.2 [M+1]⁺.

Example 2 Compound 2,(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(single enantiomer of compound 1)

1.6 g of Compound 1 (racemic) was separated by chiral supercriticalchromatography (SFC separation condition: Column: OD-10 UM, 250*20 mm,10 UM, Mobile phase: Supercritical Fluid CO₂=50:50, 70 mL/MIN, DetectorWavelength: 220 nm), and the eluting solution for the first peak wascollected and evaporated to give one enantiomer as Compound 2 (500 mg,62.5% separation yield). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.72(s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.20-7.27 (m, 6H), 7.02-7.06 (m,3H), 6.80 (d, J=7.5 Hz, 2H), 5.20 (s, 1H), 4.04-4.12 (m, 2H), 1.32-1.36(m, 3H); MS (ESI): m/z 432.1 [M+1]⁺; [α]²⁰ _(D)=−0.128 (c=0.0103 g/mL,MeOH).

Example 3 Compound 3,(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(single enantiomer of compound 1)

1.6 g of Compound 1 (racemic) was separated by chiral supercriticalchromatography (SFC separation condition: Column: OD-10 UM, 250*20 mm,10 UM, Mobile phase: Supercritical Fluid CO₂=50:50, 70 mL/MIN, DetectorWavelength: 220 nm), the eluting solution for the second peak wascollected and evaporated to give another enantiomer as Compound 3 (500mg, 62.5% separation yield). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30 (s, 1H),8.72 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.20-7.27 (m, 6H), 7.02-7.06(m, 3H), 6.80 (d, J=7.5 Hz, 2H), 5.20 (s, 1H), 4.04-4.12 (m, 2H),1.32-1.36 (m, 3H); MS (ESI): m/z 432.1 [M+1]⁺; [α]²⁰ _(D)=+0.134(c=0.01047 g/mL, MeOH).

Example 4 Compound 4,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-phenyl-2-(thiophen-2-yl)ethanone (Intermediate 1, seeExample 178 for synthesis of all Intermediates) (200 mg, 0.99 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.94 mmol), and urea(175 mg, 2.82 mmol) in anhydrous EtOH (20 mL) was added concentrated HClsolution (0.1 mL), and the reaction mixture was refluxed for three days.When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materialswere consumed, the reaction mixture was concentrated, and the crudeproduct was purified by column chromatography (EtOAc:MeOH=40:1) andpreparative HPLC to afford Compound 4 as a yellow solid (27 mg, yield6.2%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.89 (s, 1H), 7.65 (s,1H), 7.53 (s, 1H), 7.40 (s, 3H), 7.34 (s, 3H), 7.10 (d, J=5.2 Hz, 1H),6.71-6.73 (m, 1H), 6.56 (s, 1H), 5.24 (s, 1H), 4.10 (q, J=7.2 Hz, 2H);1.37 (t, J=7.2 Hz, 3H); MS (ESI): m/z 438.2 [M+1]⁺.

Example 5 Compound 5,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate 2) (100mg, 0.50 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (100 mg, 0.47mmol), and urea (90 mg, 1.4 mmol) in anhydrous EtOH (10 mL) was addedconcentrated HCl solution (0.1 mL), and the reaction mixture wasrefluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about50% of starting materials were consumed, the reaction mixture wasconcentrated and purified by column chromatography (EtOAc:MeOH=40:1) andpreparative HPLC to afford Compound 5 as a yellow solid (51 mg, yield24.8%). ¹H NMR (DMSO-d₆ 400 MHz TMS): δ 10.30 (s, 1H), 8.73 (s, 1H),7.57 (s, 1H), 7.51 (s, 1H), 7.37 (s, 3H), 7.29 (s, 3H), 7.16 (s, 1H),6.86 (s, 1H), 6.23 (d, J=4.8 Hz, 1H), 5.21 (s, 1H), 4.10 (q, J=7.2 Hz,2H); 1.37 (t, J=7.2 Hz, 3H); MS (ESI): m/z 438.1 [M+1]⁺.

Example 6 Compound 6,(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one(single enantiomer of Compound 5)

The two enantiomers of Compound 5 (racemic) were separated by chiralsupercritical fluid chromatography (SFC separation condition: Column:AD-SUM, 150*300 mm, SUM, Mobile phase: Supercritical Fluid CO₂: IPA(0.25% DEA)═70:30, 60 mL/MIN, Detector Wavelength: 220 nm), and theeluting solution for the first peak was collected and evaporated toafford one enantiomer as Compound 6 (235 mg, yield 10.8%). ¹H NMR(DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.73 (s, 1H), 7.57 (s, 1H), 7.51 (s,1H), 7.37 (s, 3H), 7.29 (s, 3H), 7.16 (s, 1H), 6.86 (s, 1H), 6.23 (d,J=4.8 Hz, 1H), 5.21 (s, 1H), 4.10 (q, J=7.2 Hz, 2H); 1.37 (t, J=7.2 Hz,3H); MS (ESI): m/z 438.1 [M+1]⁺; [α]²⁰ _(D)=−0.606 (c=0.0095 g/mL,MeOH).

Example 7 Compound 7,(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one(single enantiomer of Compound 5)

The two enantiomers of Compound 5 (racemic) were separated by chiralsupercritical fluid chromatography (SFC separation condition: Column:AD-SUM, 150*300 mm, SUM, Mobile phase: Supercritical Fluid CO₂: IPA(0.25% DEA)═70:30, 60 mL/MIN, Detector Wavelength: 220 nm), the elutingsolution for the second peak was collected and evaporated to affordanother enantiomer as Compound 7 (265 mg, yield, 12.17%). ¹H NMR(DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.73 (s, 1H), 7.57 (s, 1H), 7.51 (s,1H), 7.37 (s, 3H), 7.29 (s, 3H), 7.16 (s, 1H), 6.86 (s, 1H), 6.23 (d,J=4.8 Hz, 1H), 5.21 (s, 1H), 4.10 (q, J=7.2 Hz, 2H); 1.37 (t, J=7.2 Hz,3H); MS (ESI): m/z 438.1 [M+1]⁺; [α]²⁰ _(D)=+0.346 (c=0.0098 g/mL,MeOH).

Example 8 Compound 8,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione

A mixture of 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (323 mg, 1.53 mmol),1,2-diphenylethanone (300 mg, 1.53 mmol), thiourea (349.16 mg, 4.59mmol), concentrated HCl solution (0.8 mL) in ethanol (10 mL) wasrefluxed at 78° C. for 76 h. After being cooled down to roomtemperature, the mixture was evaporated under reduced pressure, and theresidue was purified by preparative HPLC to give Compound 8 (20 mg,yield 2.9%). 1H NMR (CD₃CN): δ 7.68 (s, 1H), 7.65 (s, 1H), 7.31 (m, 4H),7.21 (s, 1H), 7.09 (m, 3H), 6.94 (m, 2H), 5.34 (s, 1H), 4.11 (q, J=7.2Hz, 2H), 1.43-1.40 (t, J=7.2 Hz, 3H); MS (ESI): m/z 447.9 [M+1]⁺.

Example 9 Compound 9,4-(4-hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1,2-diphenylethanone (300 mg, 1.53 mmol),4-hydroxy-3-methoxy-5-nitrobenzaldehyde (301 mg, 1.53 mmol), urea (275mg, 4.587 mmol), and concentrated HCl (0.3 mL) in ethanol (10 mL) wasrefluxed for 80 h. After being cooled down to room temperature, themixture was evaporated. The residue was purified by HPLC to giveCompound 9 (262 mg, yield 41.1%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.45 (s,1H), 8.73 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.27-7.25 (m, 3H),7.23-7.21 (m, 3H), 7.06-7.00 (m, 3H), 6.83 (d, J=6.8 Hz, 2H), 5.2 (d,J=2.4 Hz, 1H), 3.80 (s, 3H); MS (ESI): m/z 417.9 [M+1]⁺.

Example 10 Compound 10,4-(3,4-dihydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (196 mg, 1.0 mmol),1,2-diphenylethanone (183 mg, 1.0 mmol) and urea (180 mg, 3.0 mmol) inethanol (50 mL) was added concentrated HCl (0.2 mL) and the reactionsolution was heated to reflux for three days. The reaction solution wasconcentrated in vacuo and purified by silica gel column chromatography(DCM:THF=20:1) to afford Compound 10 as a yellow solid (49.7 mg, 12.3%).¹H NMR (DMSO-d₆ 500 MHz): δ 10.23 (br, 1H), 8.72 (s, 1H), 7.51 (s, 1H),7.20-7.28 (m, 7H), 6.81-7.04 (m, 3H), 6.80 (d, J=6.5 Hz, 2H), 5.08 (s,1H); MS (ESI): m/z 404 [M+1]⁺.

Example 11 Compound 11,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1,2-diphenylethanone (400 mg, 2.04 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (430 mg, 2.04 mmol), and1-methylurea (454 mg, 6.12 mmol) in anhydrous EtOH was addedconcentrated HCl (204 mg, 2.04 mmol), and the reaction mixture wasrefluxed for 3 days. When TLC (EtOAc:MeOH=10:1) showed that the startingmaterials were consumed, the reaction mixture was concentrated, andpurified by preparative HPLC to afford Compound 11 as a yellow solid(138 mg, yield: 15.2%). ¹H NMR (DMSO-d₆ 400 MHz TMS): δ 10.25 (s, 1H),7.68 (d, J=2.8 Hz, 1H), 7.45 (s, 1H), 7.20-7.28 (m, 3H), 7.15-7.20 (m,3H), 6.85-6.95 (m, 3H), 6.70 (d, J=6.4 Hz, 1H), 5.00 (d, J=2.4 Hz, 1H),4.02 (m, 2H), 2.60 (s, 3H), 1.30 (t, J=7.0 Hz, 3H); MS (ESI): m/z 446.2[M+1]⁺.

Example 12 Compound 12,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 1-phenyl-2-(thiazol-2-yl)ethanone (Intermediate 3) (170mg, 0.84 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (212 mg, 1.00mmol), and urea (151 mg, 2.52 mmol) in anhydrous EtOH (20 mL) was addedconcentrated HCl solution (0.1 mL), and the reaction mixture wasrefluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about30% of the starting materials were consumed, the reaction mixture wasconcentrated, and the crude product was purified by columnchromatography and preparative HPLC to afford Compound 12 as a yellowsolid (12.5 mg, yield: 3.4%). ¹H NMR (DMSO-d₆ 400 MHz TMS): δ 10.25 (s,1H), 9.25 (s, 1H), 7.82 (s, 1H), 7.50-7.56 (m, 4H), 7.48 (s, 1H),7.36-7.40 (m, 3H), 7.22 (d, J=3.6 Hz, 1H), 5.68 (d, J=3.6 Hz, 1H), 4.10(q, J=6.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); MS (ESI): m/z 439.1 [M+1]⁺.

Example 13 Compound 13,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(2-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(2-fluorophenyl)-1-phenylethanone (200 mg, 0.93mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (196 mg, 0.93 mmol) andurea (846 mg, 1.4 mmol) in 20 mL of ethanol was added 0.2 mL ofconcentrated HCl, the mixture was stirred at reflux for 2 days. Afterthe solvent was removed under reduced pressure, the residue was purifiedby reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 13 (100 mg, yield 23.8%). ¹H NMR (DMSO-d₆ 400 MHz): δ10.26 (s, 1H), 8.81 (s, 1H), 7.53 (s, 1H), 7.35 (d, J=1.6 Hz, 1H),7.22-6.87 (m, 7H), 5.22 (s, 1H), 4.00 (m, 2H), 1.31 (t, J=7.2 Hz, 3H);MS (ESI): m/z 450.2 [M+1]⁺.

Example 14 Compound 14,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-p-tolyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-phenyl-2-p-tolylethanone (70 mg, 0.33 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (65 mg, 0.33 mmol) and urea (60mg, 1.0 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl,the mixture was stirred at reflux for 2 days. After the solvent wasremoved under reduced pressure, the residue was purified byreverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroaceticacid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound14 (21 mg, yield 14.9%). ¹H NMR (DMSO-d₆ 400 MHz TMS): δ 10.30 (s, 1H),8.67 (s, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.26-7.19 (m, 6H), 6.85-6.70(m, 4H), 5.16 (s, 1H), 4.05 (s, 2H), 2.12 (s, 3H), 1.33 (t, J=6.4 Hz,3H); MS (ESI): m/z 446.0 [M+1]⁺.

Example 15 Compound 15,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3-methoxyphenyl)-2-phenylethanone (100 mg, 0.44 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (72 mg, 0.34 mmol), urea (80 mg,1.33 mmol), and concentrated HCl solution (0.04 mL, 0.44 mmol) in EtOH(5 mL) was refluxed overnight. The mixture was evaporated in vacuo andthe residue was purified by preparative HPLC to give Compound 15 (42.57mg, yield 21%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.29 (s, 1H), 8.72 (s, 1H),7.54 (s, 1H), 7.44 (s, 1H), 7.18-7.12 (m, 2H), 7.08-7.02 (m, 3H),6.86-6.81 (m, 3H), 6.77-6.74 (m, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.05 (q,J=6.8 Hz, 2H), 3.63 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 462.1[M+1]⁺.

Example 16 Compound 16,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-p-tolyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-p-tolylethanone (65 mg, 0.31 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (54 mg, 0.26 mmol), urea (56 mg,0.93 mmol), and concentrated HCl solution (0.03 mL, 0.31 mmol) in EtOH(5 mL) was refluxed overnight. The mixture was evaporated in vacuo andthe residue was purified by preparative HPLC to give compound 16 (455.19mg, yield 40%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.28 (s, 1H), 8.64 (s, 1H),7.51 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.08-6.96 (m, 7H), 6.80 (d,J=6.8 Hz, 2H), 5.14 (d, J=2.4 Hz, 1H), 4.05-3.98 (m, 2H), 2.23 (s, 3H),1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 446.2 [M+1]⁺.

Example 17 Compound 17,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-m-tolyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-phenyl-2-m-tolylethanone (Intermediate 4) (460 mg,2.18 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (460 mg, 2.18 mmol)and urea (300 mg, 6.54 mmol) in 20 mL of ethanol was added 0.2 mL ofconcentrated HCl, the mixture was stirred at reflux for 4 days. Afterthe solvent was removed under reduced pressure, the residue was purifiedby HPLC (38-68% acetonitrile+0.1% trifluoroacetic acid in water, over 15min.) and thin layer chromatography (PE:EtOAc=1:2) to give Compound 17(25 mg, yield 2.6%). ¹H NMR (CD₃OD 400 MHz): δ 7.62 (s, 1H), 7.27 (s,5H), 7.18 (d, J=1.6 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz,1H), 6.74 (s, 1H), 6.67 (d, J=7.6 Hz, 1H), 5.36 (s, 1H), 4.07 (m, 2H),2.10 (s, 3H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 446.2 [M+1]⁺.

Example 18 Compound 18,5-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(biphenyl-4-yl)-1-phenylethanone (Intermediate 5)(430 mg, 1.57 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (333 mg,1.57 mmol), and urea (217 mg, 4.71 mmol) in 20 mL of ethanol was added0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4days. After the solvent was removed under reduced pressure, the residuewas purified by column chromatography on silica gel (PE:EtOAc=3:1˜0:1)and thin layer chromatography (PE:EtOAc=1:2) to give Compound 18 (23 mg,yield 2.9%). ¹H NMR (CD₃OD 400 MHz TMS): δ 7.61 (d, J=2.0 Hz, 1H), 7.49(d, J=7.2 Hz, 2H), 7.38-7.27 (m, 10H), 7.02 (s, 1H), 6.98 (d, J=8.0 Hz,2H), 5.23 (s, 1H), 4.02-3.99 (m, 2H), 1.38 (t, J=6.8 Hz, 3H); MS (ESI):m/z 508.2 [M+1]⁺.

Example 19 Compound 19,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(4-methoxyphenyl)-1-phenylethanone (100 mg, 0.44mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (93 mg, 0.44 mmol), andurea (60 mg, 1.32 mmol) in 20 mL of ethanol was added 0.2 mL ofconcentrated HCl, the mixture was stirred at reflux for 4 days. Afterthe solvent was removed under reduced pressure, the residue was purifiedby thin layer chromatography (PE:EtOAc=1:2) to give Compound 19 (22 mg,yield 10.8%). ¹H NMR (CD₃OD 400 MHz): δ 7.55 (s, 1H), 7.20 (s, 5H), 7.12(s, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 5.25 (s, 1H),4.05-4.00 (m, 2H), 3.61 (s, 3H), 1.35 (t, J=6.8 Hz, 3H); MS (ESI): m/z462.2 [M+1]⁺.

Example 20 Compound 20,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 1-(4-methoxyphenyl)-2-phenylethanone (200 mg, 0.88mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (187 mg, 0.89 mmol), andurea (159 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was addedconcentrated HCl solution (0.1 mL). The reaction mixture was refluxedfor two days. When TLC (EtOAc:MeOH=10:1) showed that about 30% of thestarting materials were consumed, the reaction mixture was concentrated.The residue was purified by column chromatography (EtOAc:MeOH=40:1) andpreparative HPLC to afford Compound 20 as a yellow solid (30 mg, yield:7.5%). ¹H NMR (DMSO-d₆ 300 MHz): δ 10.30 (s, 1H), 8.65 (s, 1H), 7.52 (s,1H), 7.45 (s, 1H), 7.20 (s, 1H), 7.09-7.15 (m, 2H), 6.96-7.08 (m, 3H),6.75-6.82 (m, 4H), 5.12 (s, 1H), 4.00-4.10 (m, 2H), 3.70 (s, 3H), 1.34(t, J=6.9 Hz, 3H); MS (ESI): m/z 462.0 [M+1]⁺.

Example 21 Compound 21,5-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 2-(3-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (220 mg, 1.04 mmol), and urea(159 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HClsolution (0.1 mL), and the reaction mixture was refluxed for three days.When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materialswere consumed, the reaction mixture was concentrated and purified bycolumn chromatography (EtOAc:MeOH=40:1) and preparative HPLC to affordCompound 21 as a yellow solid (90 mg, yield 22.3%). ¹H NMR (DMSO-d₆ 400MHz): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.25(d, J=4.0 Hz, 3H), 7.15-7.25 (m, 3H), 7.03 (d, J=4.8 Hz, 2H), 6.71-6.81(m, 2H), 5.25 (s, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS(ESI): m/z 466.0 [M+1]⁺.

Example 22 Compound 22,5-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(3,4-dichlorophenyl)-1-phenylethanone (Intermediate6) (400 mg, 1.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (317 mg,1.5 mmol), and urea (207 mg, 4.5 mmol) in 20 mL of ethanol was added 0.2mL of concentrated HCl, the mixture was stirred at reflux for 4 days.After the solvent was removed under reduced pressure, the residue waspurified by HPLC (48-78% acetonitrile+0.1% trifluoroacetic acid inwater, over 15 min.) and thin layer chromatography (PE:EtOAc=1:2) togive Compound 22 (17.8 mg, yield 2.4%). ¹H NMR (CD₃OD 400 MHz): δ 7.64(s, 1H), 7.35-7.31 (m, 5H), 7.23-7.19 (m, 2H), 7.03 (s, 1H), 6.79 (d,J=8.0 Hz, 1H), 5.37 (s, 1H), 4.12 (m, 2H), 1.43 (t, J=6.8 Hz, 3H); MS(ESI): m/z 500.2 [M+1]⁺.

Example 23 Compound 23,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(3-methoxyphenyl)-1-phenylethanone (400 mg, 1.77mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (374 mg, 1.77 mmol) andurea (244 mg, 5.31 mmol) in 20 mL of ethanol was added 0.2 mL ofconcentrated HCl, then the mixture was stirred at reflux for 4 days.After the solvent was removed under reduced pressure, the residue waspurified by HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid inwater, over 15 min.) and then purified by thin layer chromatography(PE:EtOAc=1:2) further to give Compound 23 (20 mg, yield 2.5%). ¹H NMR(CD₃OD 400 MHz): δ 7.43 (s, 1H), 7.17 (s, 5H), 6.86-6.82 (m, 2H), 6.48(d, J=6.4 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 6.30 (s, 1H), 5.03 (s, 1H),3.91-3.89 (m, 2H), 3.37 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI): m/z462.3 [M+1]⁺.

Example 24 Compound 24,5-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(3,4-dimethoxyphenyl)-1-phenylethanone (Intermediate7) (130 mg, 0.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (106 mg,0.5 mmol) and urea (69 mg, 1.5 mmol) in 20 mL of ethanol was added 0.2mL of concentrated HCl, then the mixture was stirred at reflux for 4days. After the solvent was removed under reduced pressure, the residuewas purified by thin layer chromatography (PE:EtOAc=1:2) to giveCompound 24 (24.3 mg, yield 9.8%). ¹H NMR (CD₃OD 400 MHz): δ 7.62 (d,J=1.6 Hz, 1H), 7.30 (s, 5H), 7.17 (s, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.51(dd, J=2.0 Hz, 8.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 5.30 (s, 1H),4.09-4.06 (m, 2H), 3.71 (s, 3H), 3.41 (s, 3H), 1.40 (t, J=7.2 Hz, 3H);MS (ESI): m/z 492.3 [M+1]⁺.

Example 25 Compound 25,5-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(4-bromophenyl)-1-phenylethanone (Intermediate 8)(140 mg, 0.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (108 mg, 0.5mmol), and urea (69 mg, 1.5 mmol) in 20 mL of ethanol was added 0.2 mLof concentrated HCl, the mixture was stirred at reflux for 3 days. Afterthe solvent was removed under reduced pressure, the residue was purifiedby HPLC (46-76% acetonitrile+0.1% trifluoroacetic acid in water, over 15min.) to give Compound 25 (43 mg, yield 16.5%). ¹H NMR (CD₃OD 400 MHz):δ 7.52 (s, 1H), 7.20-7.17 (m, 5H), 7.11-7.08 (m, 3H), 6.69 (d, J=8.4 Hz,2H), 5.23 (s, 1H), 3.40-3.95 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI):m/z 510.2 [M+1]⁺.

Example 26 Compound 26,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-o-tolyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-phenyl-2-o-tolylethanone (Intermediate 9) (100 mg,0.47 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (93.8 mg, 0.47 mmol),and urea (84.7 mg, 1.41 mmol) in 20 mL of ethanol was added 0.2 ml conHCl solution. The mixture was stirred at reflux for 2 days. After thesolvent was removed under reduced pressure, the residue was purified byreverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroaceticacid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound26 (22 mg, yield 10.4%). ¹H NMR (DMSO-d₆ 400 MHz): δ 8.60 (m, 1H),7.47-6.36 (m, 11H), 4.87 (m, 1H), 4.03-3.70 (m, 2H), 2.24 (m, 3H),1.41-1.20 (m, 3H); MS (ESI): m/z 446.0 [M+1]⁺.

Example 27 Compound 27,5-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 2-(4-chlorophenyl)-1-phenylethanone (200 mg, 0.88 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.95 mmol), and urea(156 mg, 2.65 mmol) in anhydrous EtOH (20 mL) was added concentrated HClsolution (0.1 mL), and the reaction mixture was refluxed for three days.When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materialswere consumed, the reaction mixture was concentrated, and the residuewas purified by column chromatography (EtOAc:MeOH=40:1) and preparativeHPLC to afford Compound 27 as a yellow solid (25 mg, yield: 6.25%). ¹HNMR (DMSO-d₆ 400 MHz TMS): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.60 (s, 1H),7.45 (s, 1H), 7.25-7.30 (m, 3H), 7.17-7.24 (m, 3H), 7.10 (d, J=8.8 Hz,2H), 6.80 (d, J=8.4 Hz, 2H), 5.20 (d, J=2.8 Hz, 1H), 4.00-4.11 (m, 2H),1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]⁺.

Example 28 Compound 28,5-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 2-(2-chlorophenyl)-1-phenylethanone (Intermediate 10)(85 mg, 0.37 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (94 mg, 0.45mmol), and urea (67 mg, 1.1 mmol) in anhydrous EtOH (20 mL) was addedconcentrated HCl solution (0.1 mL), and the reaction mixture wasrefluxed for three days. TLC (EtOAc:MeOH=10:1) showed that about 50% ofstarting materials were consumed, and the reaction mixture wasconcentrated. The residue was purified by column chromatography(EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 28 as a yellowsolid (12 mg, yield: 7.0%). ¹H NMR (CD₃OD 400 MHz): δ 7.47 (s, 1H),7.34-7.40 (m, 1H), 7.20 (s, 5H), 7.10-7.13 (m, 1H), 7.05 (s, 1H),6.80-6.87 (m, 1H), 6.40-6.45 (m, 1H), 5.45 (s, 1H), 3.95-4.10 (m, 2H),1.37-1.42 (m, 3H); MS (ESI): m/z 466.2 [M+1]⁺.

Example 29 Compound 29,3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile

To a solution of 3-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 11)(80 mg, 0.36 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (76 mg, 0.36mmol), and urea (50 mg, 1.08 mmol) in 20 mL of ethanol was added 0.2 mLof concentrated HCl solution, and the mixture was stirred at reflux for2 days. After the solvent was removed under reduced pressure, theresidue was purified by thin layer chromatography (PE:EtOAc=1:2) to giveCompound 29 (22 mg, yield 2.5%). ¹H NMR (CD₃OD 400 MHz): δ 7.45 (s, 1H),7.27 (d, J=7.2 Hz, 1H), 7.21-7.18 (m, 5H), 7.12-7.05 (m, 3H), 6.98 (s,1H), 5.20 (s, 1H), 3.97-3.94 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI):m/z 457.2 [M+1]⁺.

Example 30 Compound 30,5-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(3,4-difluorophenyl)-1-phenylethanone (Intermediate12) (150 mg, 0.65 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (128.1mg, 0.65 mmol), and urea (117 mg, 1.95 mmol) in 20 mL of ethanol wasadded 0.2 ml con. HCl. The mixture was refluxed for 2 days. After thesolvent was removed under reduced pressure, the residue was purified byreverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroaceticacid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound30 (132 mg, yield 43.3%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30 (s, 1H),8.82 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.30-7.20 (m, 6H), 7.07 (m,1H), 6.86 (m, 1H), 6.59 (s, 1H), 5.27 (s, 1H), 4.08 (m, 2H), 1.33 (t,J=6.8 Hz, 3H); MS (ESI): m/z 468.0 [M+1]⁺

Example 31 Compound 31,6-(3,5-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(3,5-dichlorophenyl)-2-phenylethanone (Intermediate13) (100 mg, 0.38 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (74.6mg, 0.38 mmol) and urea (68.0 mg, 1.13 mmol) in 20 mL of ethanol wasadded 0.2 mL of concentrated HCl solution, and the mixture was refluxedfor 2 days. After the solvent was removed under reduced pressure, theresidue was purified by reverse-phase preparatory HPLC (26-53%acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroaceticacid, over 15 min.) to give compound 31 (53 mg, yield 26.4%). ¹H NMR(DMSO-d₆ 400 MHz): δ 10.26 (s, 1H), 8.57 (s, 1H), 7.57 (s, 1H), 7.50 (s,1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.19 (s, 1H), 7.07-7.11 (m, 4H), 6.88(d, J=6.8 Hz, 2H), 5.27 (d, J=2.0 Hz, 1H), 4.03 (m, 2H), 1.31 (t, J=7.2Hz, 1H); MS (ESI): m/z 499.9 [M+1]⁺.

Example 32 Compound 32,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3-fluorophenyl)-2-phenylethanone (100 mg, 0.47 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (82 mg, 0.39 mmol), urea (70 mg,1.17 mmol), and concentrated HCl solution (0.03 mL, 0.39 mmol) in EtOH(5 mL) was refluxed overnight. The mixture was evaporated in vacuo andpurified by preparative HPLC to give Compound 32 (22.35 mg, yield 13%)as a yellow solid. ¹H NMR (DMSO-d₆ 400 MHz): δ 10.28 (s, 1H), 8.79 (s,1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.30-7.25 (m, 1H), 7.16 (s, 1H),7.12-6.99 (m, 6H), 6.86 (d, J=7.6 Hz, 2H), 5.23 (d, J=2.4 Hz, 1H), 4.04(q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 450.0 [M+1]⁺.

Example 33 Compound 33,6-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-bromophenyl)-2-phenylethanone (100 mg, 0.36 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (64 mg, 0.30 mmol), urea (55 mg,0.91 mmol), and concentrated HCl solution (0.03 mL, 0.36 mmol) in EtOH(5 mL) was refluxed overnight. The mixture was evaporated in vacuo, andpurified by preparative HPLC to give Compound 33 (52.12 mg, yield 34%).¹H NMR (DMSO-d₆ 400 MHz): δ 10.29 (s, 1H), 8.78 (s, 1H), 7.56 (s, 1H),7.46-7.42 (m, 3H), 7.15-7.13 (m, 3H), 7.09-7.03 (m, 3H), 6.84 (d, J=6.8Hz, 2H), 5.21 (d, J=2.0 Hz, 1H), 4.07-3.99 (m, 2H), 2.23 (s, 3H), 1.33(t, J=6.8 Hz, 3H); MS (ESI): m/z 511.9 [M+1]⁺.

Example 34 Compound 34,6-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(biphenyl-4-yl)-2-phenylethanone (Intermediate 14) (100mg, 0.37 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (65 mg, 0.31mmol), urea (66 mg, 1.1 mmol), and concentrated HCl solution (0.03 mL,0.37 mmol) in EtOH (5 mL) was refluxed overnight. The mixture wasevaporated in vacuo, and purified by preparative HPLC to give Compound34 (22.52 mg, yield 14%). ¹H NMR (DMSO-d₆ 300 MHz): δ 10.33 (s, 1H),8.79 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.61-7.58 (m, 3H), 7.47-7.43 (m,3H), 7.37 (d, J=6.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.22 (s, 1H),7.09-7.02 (m, 3H), 6.89 (d, J=7.8 Hz, 2H), 5.21 (d, J=2.7 Hz, 1H), 4.06(q, J=3.6 Hz, 2H), 1.34 (t, J=6.9 Hz, 3H); MS (ESI): m/z 508.1 [M+1]⁺.

Example 35 Compound 35,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-fluorophenyl)-2-phenylethanone (200 mg, 0.93 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (164 mg, 0.78 mmol), urea (140mg, 2.3 mmol), and concentrated HCl solution (0.08 mL, 0.93 mmol) inEtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo,and the residue was purified by preparative HPLC to give Compound 35(120 mg, yield 29%). ¹H NMR (DMSO-d₆ 300 MHz): δ 10.28 (s, 1H), 8.76 (s,1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.25-7.21 (m, 2H), 7.16 (s, 1H),7.11-6.97 (m, 5H), 6.81 (d, J=7.5 Hz, 2H), 5.19 (s, 1H), 4.08-3.99 (m,2H), 1.32 (t, J=6.6 Hz, 3H); MS (ESI): m/z 450.0 [M+1]⁺.

Example 36 Compound 36,6-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-chlorophenyl)-2-phenylethanone (350 mg, 1.52 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (320 mg, 1.52 mmol), and urea(272 mg, 4.53 mmol) in anhydrous EtOH (15 mL) was added concentrated HClsolution (0.5 mL), and the reaction mixture was refluxed for overnight.TLC (EtOAc:MeOH=10:1) showed that about 30% of starting materials wereconsumed, and the reaction mixture was concentrated. The residue waspurified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLCto afford the product Compound 36 as a yellow solid (55.1 mg, yield:7.8%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.79 (s, 1H), 7.55 (s,1H), 7.42 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.18(s, 1H), 7.00-7.10 (m, 3H), 6.82 (d, J=7.2 Hz, 2H), 5.20 (d, J=2.4 Hz,1H), 4.00-4.10 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0[M+1]⁺.

Example 37 Compound 37,6-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3-chlorophenyl)-2-phenylethanone (450 mg, 1.95 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (411 mg, 1.95 mmol), and urea(350 mg, 5.83 mmol) in anhydrous EtOH (15 mL) was added concentrated HClsolution (0.5 mL), the reaction mixture was refluxed overnight. TLC(EtOAc:MeOH=10:1) showed that about 30% of starting materials wereconsumed, and the reaction mixture was concentrated. The residue waspurified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLCto afford Compound 37 as a yellow solid (78.1 mg, yield: 8.6%). ¹H NMR(DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.42 (d,J=1.2 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.20-7.25 (m, 2H), 7.02-7.7.13(m, 5H), 6.85 (d, J=6.8 Hz, 2H), 5.25 (d, J=2.8 Hz, 1H), 4.00-4.10 (m,2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+1]⁺.

Example 38 Compound 38,6-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3,4-dimethoxyphenyl)-2-phenylethanone (180 mg, 0.7mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (124 mg, 0.59 mmol), urea(105 mg, 1.8 mmol), and concentrated HCl solution (0.05 mL, 0.59 mmol)in EtOH (5 mL) was refluxed overnight. The mixture was evaporated invacuo, and the residue was purified by preparative HPLC to give Compound38 (100 mg, yield 35%) as a yellow solid. ¹H NMR (CD₃OD 400 MHz): δ 7.63(d, J=1.2 Hz, 1H), 7.19 (s, 1H), 7.13-7.06 (m, 3H), 6.93-6.85 (m, 4H),6.73 (s, 1H), 5.34 (s, 1H), 4.11-4.02 (m, 2H), 3.80 (s, 3H), 3.57 (s,3H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 492.0 [M+1]⁺.

Example 39 Compound 39,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluoro-4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3-fluoro-4-methoxyphenyl)-2-phenylethanone (100 mg, 0.41mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (72 mg, 0.34 mmol), urea(61 mg, 1.02 mmol), and concentrated HCl solution (0.03 mL, 0.34 mmol)in EtOH (5 mL) was refluxed overnight. The mixture was evaporated invacuo, and the residue was purified by preparative HPLC to give Compound39 (78 mg, yield 48%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.28 (s, 1H), 8.71(s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.10-7.01 (m, 5H),6.95 (d, J=9.2 Hz, 1H), 6.85 (d, J=6.8 Hz, 2H), 5.18 (s, 1H), 4.08-4.01(m, 2H), 3.79 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 480.0[M+1]⁺.

Example 40 Compound 40,4-(3-fluoro-5-hydroxy-4-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (127 mg, 0.75mmol), 1,2-diphenylethaone (176 mg, 0.9 mmol) and urea (135 mg, 2.25mmol) in ethanol (10 mL) was added concentrated HCl (0.4 mL) and thereaction solution was heated to reflux for 3 days. The reaction solutionwas concentrated in vacuo and purified by silica gel columnchromatography (DCM:MeOH=10:1) to afford Compound 40 as a white solid(21 mg, 7%). ¹H NMR (DMSO-d₆ 500 MHz): δ 7.28 (br, 3H), 7.22 (br, 2H),7.04 (m, 3H), 6.82 (d, 2H, J=5 Hz), 6.79-6.83 (m, 3H), 5.10 (s, 1H); MS(ESI): m/z 391.1 [M+1]⁺.

Example 41 Compound 41,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1,3-dimethyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1,2-diphenylethanone (300 mg, 1.53 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (324 mg, 1.53 mmol), and1,3-dimethylurea (174 mg, 1.98 mmol) in DMF (5 mL) was added TMSCl (1.0g, 9.12 mmol), and the reaction mixture was stirred at room temperatureovernight under nitrogen. LCMS showed that about 30% of startingmaterials were consumed. H₂O (10 mL) was added to quench the reaction,and the aqueous layer was extracted with EtOAc (30 mL×3). The combinedorganic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography (PE:EtOAc=1:2) and preparative HPLC to afford Compound 41as a yellow solid (82 mg, yield: 11.6%). ¹H NMR (DMSO-d₆ 400 MHz):δ10.40 (s, 1H), 7.50 (s, 1H), 7.30 (d, J=6.0 Hz, 3H), 7.25 (d, J=8.0 Hz,3H), 7.00 (d, J=6.8 Hz, 3H), 6.75 (d, J=6.4 Hz, 2H), 5.11 (s, 1H),4.00-4.17 (m, 2H), 2.82 (s, 3H), 2.75 (s, 3H), 1.33 (t, J=6.8 Hz, 3H);MS (ESI): m/z 460.1 [M+1]⁺.

Example 42 Compound 42,4-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile

To a solution of 4-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 15)(70 mg, 0.32 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (68 mg, 0.32mmol), and urea (44 mg, 0.96 mmol) in 20 mL of ethanol was added 0.2 mLof concentrated HCl solution, and the mixture was stirred at 130° C. for2 days. After the solvent was removed under reduced pressure, theresidue was purified by preparative HPLC (35-75% acetonitrile+0.1%trifluoroacetic acid in water, over 15 min.) to give the compound 42 (16mg, yield 11%). ¹H NMR (CD₃OD 400 MHz): δ 7.64 (s, 1H), 7.41 (d, J=7.6Hz, 2H), 7.34-7.31 (m, 5H), 7.25 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 5.41(s, 1H), 4.14-4.09 (m, 2H), 1.43 (t, J=7.2 Hz, 3H); MS (ESI): m/z 457.2[M+1]⁺.

Example 43 Compound 43,6-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(4-chloro-3-fluorophenyl)-2-phenylethanone(Intermediate 16) (100 mg, 0.40 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (79.5 mg, 0.40 mmol), and urea(73.2 mg, 1.20 mmol) in 5 mL of ethanol was added 0.2 mL of concentratedHCl solution, and the mixture was refluxed for 2 days. After the solventwas removed under reduced pressure, the residue was purified byreverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroaceticacid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound43 (18 mg, yield 9.3%). ¹H NMR (DMSO-d₆ 300 MHz) δ 10.29 (s, 1H), 8.83(s, 1H), 7.57 (s, 1H), 7.44 (m, 2H), 7.28 (d, J=9.9 Hz, 1H), 7.13-6.86(m, 4H), 5.26 (s, 1H), 4.04 (m, 2H), 1.32 (t, J=6.3 Hz, 3H); MS (ESI):m/z 483.9 [M+1]⁺.

Example 44 Compound 44,6-(3-chloro-4-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(3-chloro-4-fluorophenyl)-2-phenylethanone(Intermediate 17) (65 mg, 0.26 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (51.6 mg, 0.26 mmol), and urea(47.6 mg, 0.78 mmol) in 5 mL of ethanol was added 0.2 mL of concentratedHCl solution, and the mixture was refluxed for 2 days. After the solventwas removed under reduced pressure, the residue was purified byreverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroaceticacid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound44 (22 mg, yield 17.4%). ¹H NMR (DMSO-d₆ 300 MHz): δ 10.28 (s, 1H), 8.83(s, 1H), 7.57 (s, 1H), 7.43 (m, 2H), 7.28 (t, J=9.0 Hz, 1H), 7.17-7.04(m, 5H), 6.87 (d, J=6.3 Hz, 2H), 5.25 (d, J=2.4 Hz, 1H), 4.04 (m, 2H),1.32 (t, J=6.9 Hz, 3H); MS (ESI): m/z 483.9[M+1]⁺.

Example 45 Compound 45,6-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(3,4-difluorophenyl)-2-phenylethanone (120 mg, 0.52mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (101.8 mg, 0.52 mmol), andurea (95.1 mg, 1.56 mmol) in 5 mL of ethanol was added 0.2 mL ofconcentrated HCl solution, and the mixture was refluxed for 2 days.After the solvent was removed under reduced pressure, the residue waspurified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 45 (35 mg, yield 14.5%). ¹H NMR (DMSO-d₆ 400 MHz TMS):δ 10.27 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.31 (m, 2H),7.14 (s, 1H), 7.11-6.99 (m, 3H), 6.87 (m, 1H), 6.86 (d, J=7.2 Hz, 2H),5.24 (d, J=2.0 Hz, 1H), 4.04 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI):m/z 468.0[M+1]⁺.

Example 46 Compound 46,6-(3,5-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(3,5-difluorophenyl)-2-phenylethanone (Intermediate18) (100 mg, 0.43 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (84.9mg, 0.43 mmol), and urea (78.6 mg, 1.29 mmol) in 5 mL of ethanol wasadded 0.2 mL of concentrated HCl, and the mixture was refluxed for 2days. After the solvent was removed under reduced pressure, the residuewas purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 46 (40 mg, yield 19.9%). ¹H NMR (DMSO-d₆ 400 MHz) δ10.27 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.31 (m, 2H),7.14 (s, 1H), 7.11-6.99 (m, 4H), 6.86 (d, J=7.2 Hz, 2H), 5.24 (s, 1H),4.04 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 468.0 [M+1]⁺.

Example 47 Compound 47,6-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(3,4-dichlorophenyl)-2-phenylethanone (Intermediate19) (100 mg, 0.38 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (74.4mg, 0.38 mmol), and urea (68.5 mg, 1.14 mmol) in 5 mL of ethanol wasadded 0.2 mL of concentrated HCl solution, and the mixture was refluxedfor 2 days. After the solvent was removed under reduced pressure, theresidue was purified by reverse-phase preparatory HPLC (26-53%acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroaceticacid, over 15 min.) to give Compound 47 (32 mg, yield 17.0%). ¹H NMR(DMSO-d₆ 300 MHz) δ 10.28 (s, 1H), 8.85 (s, 1H), 7.58 (s, 1H), 7.48 (t,J=7.5 Hz, 2H), 7.41 (d, J=1.8 Hz, 1H), 7.13-7.05 (m, 5H), 6.88 (t, J=1.8Hz, 2H), 5.25 (d, J=2.7 Hz, 1H), 4.02 (m, 2H), 1.32 (t, J=6.9 Hz, 3H);MS (ESI): m/z 499.9 [M+1]⁺.

Example 48 Compound 48,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-(methoxymethoxy)phenyl)-2-phenylethanone (Intermediate20) (100 mg, 0.39 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (69 mg,0.33 mmol), urea (59 mg, 0.98 mmol), and concentrated HCl solution (0.03mL, 0.33 mmol) in EtOH (5 mL) was refluxed overnight. The mixture wasevaporated in vacuo, and the residue was purified by preparative HPLC togive Compound 48 (65.12 mg, yield 45%). ¹H NMR (CD₃OD 400 MHz): δ 7.62(s, 1H), 7.20 (s, 1H), 7.10-7.05 (m, 5H), 6.90 (d, J=6.8 Hz, 2H), 6.66(d, J=8.0 Hz, 2H), 5.31 (s, 1H), 4.11-4.04 (m, 2H), 1.41 (t, J=6.8 Hz,3H); MS (ESI): m/z 448.0[M+1]⁺.

Example 49 Compound 49,6-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(2,4-difluorophenyl)-2-phenylethanone (Intermediate 21)(250 mg, 1.1 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (189 mg, 0.90mmol), urea (162 mg, 2.69 mmol), and concentrated HCl solution (0.075mL, 0.90 mmol) in EtOH (10 mL) was refluxed overnight. The mixture wasevaporated in vacuo, and the residue was purified by preparative HPLC togive Compound 49 (30.03 mg, yield 7%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.32(s, 1H), 8.91 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.43-7.37 (m, 1H),7.29 (s, 1H), 7.11-6.89 (m, 5H), 6.88 (d, J=7.2 Hz, 2H), 5.27 (s, 1H),4.08 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H); MS (ESI): m/z 468.1[M+1]⁺.

Example 50 Compound 50,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-3-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(furan-3-yl)-2-phenylethanone (Intermediate 22) (692 mg,3.72 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (942 mg, 4.46 mmol),and urea (669.6 mg, 11.16 mmol) in anhydrous EtOH (5 mL) was addedconcentrated HCl solution (0.2 mL), and the reaction mixture wasrefluxed (110° C.) for thirteen hours. TLC (eluting with EtOAc) showedthat the most of the starting materials were consumed. The reactionmixture was concentrated, and purified by column chromatography andpreparative HPLC to afford Compound 50 as a yellow solid (173 mg, yield:11.0%). ¹H NMR (DMSO-d₆ 400 MHz TMS): δ10.26 (s, 1H), 8.478 (s, 1H),6.981-7.708 (m, 10H), 5.766 (s, 1H), 5.141 (d, J=2.4 Hz, 1H),3.918-4.061 (m, 2H), 1.304 (t, J=6.8 Hz, 3H); MS (ESI): m/z 422.1[M+1]⁺.

Example 51 Compound 51,6-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(2-chlorophenyl)-2-phenylethanone (100 mg, 0.43mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (91 mg, 0.43 mmol), andurea (60 mg, 1.29 mmol) in 10 mL of ethanol was added 0.2 mL ofconcentrated HCl solution. The mixture was stirred at 130° C. for 2days, concentrated under reduced pressure, and purified by preparativeHPLC (40-70% acetonitrile+0.1% trifluoroacetic acid in water, over 15min.) to give Compound 51 (28.7 mg, yield 14.2%). ¹H NMR (CD₃OD 400MHz): δ 7.43 (s, 1H), 7.19-7.04 (m, 5H), 6.79 (d, J=6.0 Hz, 3H), 6.72(s, 2H), 5.23 (s, 1H), 3.88-3.85 (m, 2H), 1.81 (t, J=6.8 Hz, 3H); MS(ESI): m/z 466.2 [M+1]⁺.

Example 52 Compound 52,3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide

A mixture of3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile(Compound 29) (40 mg, 0.088 mmol), H₂O₂ (0.5 mL), and K₂CO₃ (36 mg, 0.27mmol) in DMSO (1 mL) was stirred at room temperature overnight. Themixture was quenched with aqueous saturated Na₂SO₃ solution, and thesolution was extracted with a mixture of CH₂Cl₂/i-PrOH (3:1). Theorganic layer was concentrated in vacuo, and the mixture was purified bythin layer chromatography (ethyl acetate) to give compound 52 (20 mg,yield 47.6%). ¹H NMR (CD₃OD 400 MHz): δ 7.64 (s, 1H), 7.56 (s, 2H), 7.28(s, 5H), 7.20 (s, 1H), 7.12 (t, J=7.2 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H),5.43 (s, 1H), 4.11-4.03 (m, 2H), 1.40 (t, J=7.2 Hz, 3H); MS (ESI): m/z475.3 [M+1]⁺.

Example 53 Compound 53,3-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile

To a solution of 3-(2-phenylacetyl)benzonitrile (Intermediate 23) (100mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (89.1 mg, 0.45mmol), and urea (82.3 mg, 1.35 mmol) in 5 mL of ethanol was added 0.2 mLof concentrated HCl, the mixture was refluxed for 2 days. After thesolvent was removed under reduced pressure, the residue was purified byreverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroaceticacid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound53 (18.2 mg, yield 8.8%). ¹H NMR (DMSO-d₆ 400 MHz) δ 10.27 (s, 1H), 8.86(s, 1H), 7.71 (t, J=12.4 Hz, 2H), 7.57 (s, 1H), 7.44 (m, 3H), 7.14-7.06(m, 4H), 6.85 (d, J=6.8 Hz, 2H), 5.28 (s, 1H), 4.06 (m, 2H), 1.32 (t,J=6.8 Hz, 3H); MS (ESI): m/z 456.9 [M+1]⁺.

Example 54 Compound 54,6-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(4-(dimethylamino)phenyl)-2-phenylethanone (80 mg,0.32 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (63 mg, 0.32 mmol),and urea (60 mg, 0.96 mmol) in 5 mL of ethanol was added 0.2 mL ofconcentrated HCl solution, and the mixture was refluxed for 2 days.After the solvent was removed under reduced pressure, the residue waspurified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 54 (27 mg, yield 16.3%). ¹H NMR (DMSO-d₆ 400 MHz TMS):δ 10.29 (s, 1H), 8.51 (s, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.23 (s, 1H),7.07-6.97 (m, 5H), 6.83 (d, J=7.2 Hz, 2H), 6.58 (d, J=8.4 Hz, 2H), 5.07(d, J=2.4 Hz, 1H), 4.05 (q, J=6.8 Hz, 2H), 2.88 (s, 6H), 1.34 (t, J=6.8Hz, 3H); MS (ESI): m/z 475.0 [M+1]⁺.

Example 55 Compound 55,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(2-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(2-fluorophenyl)-2-phenylethanone (Intermediate 24)(100 mg, 0.47 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (92.0 mg,0.47 mmol), and urea (85.4 mg, 1.40 mmol) in 5 mL of ethanol was added0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2days. After the solvent was removed under reduced pressure, the residuewas purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 55 (83 mg, yield 39.7%). ¹H NMR (DMSO-d₆ 400 MHz) δ10.25 (s, 1H), 8.77 (s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 7.29 (d, J=5.2Hz, 1H), 7.21-7.6.80 (m, 7H), 6.79 (d, J=6.8 Hz, 2H), 5.18 (s, 1H), 4.01(m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI): m/z 450.0 [M+1]⁺.

Example 56 Compound 56,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-morpholinophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-morpholinophenyl)-2-phenylethanone (Intermediate 25)(280 mg, 1.00 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (175 mg,0.83 mmol), urea (179 mg, 2.99 mmol), and concentrated HCl solution(0.07 mL, 0.83 mmol) in EtOH (5 mL) was refluxed for 48 h. The mixturewas evaporated in vacuo, and the residue was purified by preparativeHPLC to give Compound 56 (55.29 mg, yield 13%) as a solid. ¹H NMR (CD₃OD300 MHz): δ 7.62 (d, J=2.1 Hz, 1H), 7.20-7.15 (m, 3H), 7.10-7.04 (m,3H), 6.92-6.85 (m, 4H), 5.30 (s, 1H), 4.12-4.02 (m, 2H), 3.81 (t, J=4.8Hz, 4H), 3.15 (t, J=4.8 Hz, 4H), 1.41 (t, J=6.9 Hz, 3H); MS (ESI): m/z517.0 [M+1]⁺.

Example 57 Compound 57,6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

Step 1:

A mixture of6-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 33) (550 mg, 1.08 mmol), diphenylmethanimine (236 mg, 1.3mmol), Cs₂CO₃ (702 mg, 2.16 mmol), Pd₂(dba)₃ (198 mg, 0.22 mmol), andxantphos (250 mg, 0.43 mmol) in dioxane (10 mL) was degassed andrefluxed overnight under nitrogen. When LCMS indicated the startingmaterial was consumed, the mixture was diluted with water, and extractedwith EtOAc. The organic layer was concentrated, and purified by columnto give6-(4-(diphenylmethyleneamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one(230 mg, yield 35%) as a yellow solid.

Step 2:

To a solution of6-(4-(diphenylmethyleneamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one(230 mg, 0.38 mmol) in THF (2 mL) was added concentrated HCl solution(0.5 mL), and the mixture was stirred at room temperature for 2 h. Themixture was concentrated and purified by column to give Compound 57 (170mg, yield 100%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.31 (s, 1H), 8.54 (s,1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.07-6.97 (m,5H), 6.83 (d, J=7.2 Hz, 2H), 6.59 (d, J=7.2 Hz, 2H), 5.09 (d, J=2.8 Hz,1H), 4.06 (q, J=6.8 Hz, 2H), 1.34 (t, J=6.8 Hz, 3H); MS (ESI): m/z 447.0[M+1]⁺.

Example 58 Compound 58,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyrazin-2-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-phenyl-2-(pyrazin-2-yl)ethanone (Intermediate 26)(150 mg, 0.76 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (149 mg,0.76 mmol), and urea (137 mg, 2.28 mmol) in 20 mL of ethanol was added0.2 mL of concentrated HCl solution, the reaction mixture was stirred atreflux for 2 days. After the solvent was removed under reduced pressure,the residue was purified by reverse-phase preparatory HPLC (26-53%acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroaceticacid, over 15 min.) to give Compound 58 (72 mg, yield 21.9%). ¹H NMR(DMSO-d₆300 MHz): δ10.27 (S, 1H), 9.22 (s, 1H), 8.43 (s, 1H), 8.15 (s,1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.44 (m, 4H), 7.32 (d, J=7.2 Hz, 3H),5.45 (d, J=2.1 Hz, 1H), 4.10 (m, 2H), 1.35 (t, J=6.9 Hz, 3H); MS (ESI):m/z 434.0 [M+1]⁺.

Example 59 Compound 59,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-2-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(pyridin-2-yl)ethanone (Intermediate 27) (200mg, 1.01 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (214.1 mg, 1.01mmol), urea (182.5 mg, 3.04 mmol), and concentrated hydrochloric acidsolution (0.3 mL) in ethanol (1 mL) was refluxed for 60 h. After beingcooled down to room temperature, the mixture was evaporated, andpurified by preparative HPLC to give Compound 59 (132.5 mg, yield30.2%). ¹H NMR (DMSO-d₆ 400 MHz): δ10.26 (brs, 1H), 8.59 (d, J=4.4 Hz,1H), 8.37 (s, 1H), 7.62-7.54 (m, 2H), 7.42 (s, 1H), 7.30-7.27 (m, 1H),7.14 (d, J=6.4 Hz, 4H), 6.93-6.90 (m, 3H), 5.25 (s, 1H), 4.03-3.99 (m,2H), 1.33-1.29 (m, 3H); MS (ESI): m/z 433.0 [M+H]⁺.

Example 60 Compound 60,5-(biphenyl-3-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(biphenyl-3-yl)-1-phenylethanone (Intermediate 28)(120 mg, 0.44 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (86.9 mg,0.44 mmol), and urea (79.3 mg, 1.32 mmol) in 5 mL of ethanol was added0.2 mL of concentrated HCl solution. The mixture was refluxed for 2days. After the solvent was removed under reduced pressure, the residuewas purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 60 (25 mg, yield 11.2%). ¹H NMR (DMSO-d₆ 400 MHz) δ10.24 (s, 1H), 8.74 (s, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.32-7.12 (m,12H), 7.10 (t, J=8.0 Hz, 1H), 7.00 (m, 1H), 6.82 (d, J=6.8 Hz, 1H), 5.30(d, J=2.8 Hz, 1H), 4.00 (m, 2H), 1.26 (t, J=6.8 Hz, 3H); MS (ESI): m/z508.1 [M+1]⁺.

Example 61 Compound 61,6-(benzo[d][1,3]dioxol-5-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-2-phenylethanone(Intermediate 29) (400 mg, 1.7 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (352 mg, 1.7 mmol), and urea (230mg, 5.0 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HClsolution, the mixture was stirred at 130° C. overnight. After thesolvent was removed under reduced pressure, the residue was purified bypreparative HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid inwater, over 15 min.) to give Compound 61 (92.5 mg, yield 11.7%). ¹H NMR(CD₃OD 400 MHz): δ 7.60 (s, 1H), 7.18 (s, 1H), 7.12-7.09 (m, 3H), 6.92(d, J=7.2 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.71 (m, 2H), 5.92 (s, 2H),5.32 (s, 1H), 4.11-4.03 (m, 2H), 1.41 (t, J=7.2 Hz, 3H); MS (ESI): m/z476.3 [M+1]⁺.

Example 62 Compound 62,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-3-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

Step 1:

To a solution of 1,2-diphenylethanone (300 mg, 1.5 mmol) and3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (324 mg, 1.5 mmol) in anhydroustoluene (10 mL) was added piperidine (cat.), and the reaction mixturewas refluxed overnight. TLC (PE:EtOAc=3:1) indicated that the startingmaterials were consumed. The solvent was removed under vacuum, and theresidue was purified by column chromatography (PE:EtOAc=10:1) to affordthe intermediate as a red solid (420 mg, yield: 70.6%). ¹H NMR (DMSO-d₆400 MHz): δ 10.50 (s, 1H), 7.90 (d, J=1.4 Hz, 3H), 7.80 (d, J=1.2 Hz,2H), 7.58-7.61 (m, 2H), 7.25-7.7.50 (m, 21H), 7.20 (s, 1H), 7.05 (s,1H), 6.75 (s, 1H), 3.80 (q, J=7.2 Hz, 3H), 3.62 (q, J=7.2 Hz, 2H), 1.17(t, J=3.6 Hz, 7H), 1.12 (t, J=3.6 Hz, 3H); MS (ESI): m/z 390.1 [M+1]⁺.

Step 2:

To a solution of the Intermediate prepared in Step 1 (480 mg, 1.2 mmol)and 1-methylurea (274 mg, 3.7 mmol) in anhydrous toluene (10 mL) wasadded NaH (99 mg, 4.8 mmol), then a few drops of MeOH were added toinitiate the reaction, and the mixture was stirred at 60° C. overnight.TLC (EtOAc:MeOH=1:2) showed the starting materials were consumed. Thereaction mixture was poured into ice-water, and acidified with 0.5 N HClto pH=2. The aqueous layer was extracted with EtOAc (20 mL×3), thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography and preparative HPLC to afford Compound 62 as a yellowsolid (55.2 mg, yield: 10.1%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30 (s,1H), 8.79 (s, 1H), 7.45 (s, 1H), 7.12-7.21 (m, 6H), 6.95-7.05 (m, 3H),6.75 (d, J=6.4 Hz, 2H), 5.21 (s, 1H), 3.97-4.05 (m, 2H), 2.75 (s, 3H)1.30 (t, J=7.2 Hz, 3H); MS (ESI): m/z 466.1 [M+1]⁺.

Example 63 Compound 63,4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile

A mixture of 4-(2-phenylacetyl)benzonitrile (Intermediate 30) (50 mg,0.23 mmol), 1,2-diphenylethanone (43 mg, 0.21 mmol), urea (41 mg, 0.68mmol), and concentrated HCl solution (0.02 mL, 0.21 mmol) in EtOH (5 mL)was heated at reflux for 48 h. The mixture was evaporated in vacuo, andthe residue was purified by preparative HPLC to give Compound 63 (22.27mg, yield 40%). ¹H NMR (CD₃OD 400 MHz): δ 7.62-7.59 (m, 3H), 7.42 (d,J=8.0 Hz, 2H), 7.13-7.10 (m, 4H), 6.92-6.90 (m, 2H), 5.41 (s, 1H),4.10-4.00 (m, 2H), 1.40 (t, J=7.2 Hz, 3H); MS (ESI): m/z 457.0 [M+1]⁺.

Example 64 Compound 64,4-(3-ethoxy-5-fluoro-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

The mixture of 3-ethoxy-5-fluoro-4-hydroxybenzaldehyde (Intermediate 32)(160 mg, 0.87 mmol), 1,2-diphenyl-ethanone (170 mg, 0.87 mmol), urea(157 mg, 2.61 mmol), and concentrated HCl solution (0.2 mL) in ethanol(20 mL) was degassed and refluxed for 3 days under N₂ protection. Thesolvent was removed under reduced pressure, and the residue was purifiedby preparative HPLC to give Compound 64 (30 mg, 10.6%). ¹H NMR (DMSO-d₆300 MHz) δ 9.08 (s, br, 1H), 8.63 (s, 1H), 7.42 (s, 1H), 7.19-7.26 (m,5H), 7.01-7.03 (m, 3H), 6.72-6.81 (m, 4H), 5.04 (d, J=2.7 Hz, 1H), 3.99(q, J₁=6.9 Hz, J₂=9.0 Hz, 2H), 1.33 (t, J=6.9 Hz, 3H); MS (ESI): m/z405.1 [M+1]⁺.

Example 65 Compound 65,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(pyridin-3-yl)ethanone (Intermediate 31) (110mg, 0.56 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (107 mg, 0.51mmol), urea (91 mg, 1.52 mmol), and concentrated HCl solution (0.04 mL,0.56 mmol) in EtOH (5 mL) was refluxed overnight. The mixture wasevaporated in vacuo and purified by preparative HPLC to give Compound 65(46.21 mg, yield 21%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.28 (s, 21H), 8.91(s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 7.71 (d, J=7.2 Hz, 1H),7.59 (s, 1H), 7.43 (s, 1H), 7.36 (t, J=5.2 Hz, 1H), 7.15 (s, 1H),7.09-7.04 (m, 3H), 6.86 (d, J=6.8 Hz, 2H), 5.29 (d, J=2.0 Hz, 1H), 4.04(q, J=6.8 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 433.0 [M+1]⁺.

Example 66 Compound 66,(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one(single enantiomer of Compound 65)

The two enantiomers of Compound 65 were separated by chiralsupercritical chromatography (SFC separation condition: Column: AS-20UM, 300*300 mm, 20 UM; Mobile Phase: Supercritical Fluid CO2:MeOH=65:35,80 ML/MIN; Detector Wavelength: 220 nm), the eluting solution for thefirst peak was collected and evaporated to give one enantiomer asCompound 66 (37 mg, yield 6%). ¹H NMR (CD₃OD 400 MHz): δ 8.32 (d, J=4.4Hz, 1H), 8.26 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.30-7.26(m, 1H), 7.03-7.01 (m, 4H), 6.83-6.81 (m, 2H), 5.34 (s, 1H), 4.02-3.91(m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI): m/z 433.0 [M+1]⁺.

Example 67 Compound 67,(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one(single enantiomer of Compound 65)

The two enantiomers of Compound 65 were separated by chiralsupercritical chromatography (SFC separation condition: Column: AS-20UM, 300*300 mm, 20 UM; Mobile Phase: Supercritical Fluid CO2:MeOH=65:35,80 ML/MIN; Detector Wavelength: 220 nm), the eluting solution for thesecond peak was collected and evaporated to give another enantiomer asCompound 67 (35 mg, yield 6%). ¹H NMR (CD₃OD 400 MHz): δ 8.29 (d, J=4.4Hz, 1H), 8.23 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.26-7.23(m, 1H), 7.00-6.99 (m, 4H), 6.82-6.79 (m, 2H), 5.30 (s, 1H), 3.98-3.88(m, 2H), 1.28 (t, J=6.8 Hz, 3H); MS (ESI): m/z 433.0 [M+1]⁺.

Example 68 Compound 68,4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (50 mg, 0.294mmol), 1,2-diphenylethanone (57.7 mg, 0.294 mmol), urea (52.9 mg, 0.882mmol), and concentrated HCl solution (0.5 mL) in ethanol (2 mL) wasrefluxed at 80° C. for 52 h. The reaction mixture was evaporated underreduced pressure, and the residue was purified by preparative HPLC togive Compound 68 (32.1 mg, yield 28%). ¹HNMR (DMSO-d₆ 400 MHZ): δ 9.25(s, 1H), 8.70 (s, 1H), 7.49 (s, 1H), 7.32-7.26 (m, 5H), 7.11-7.05 (m,3H), 6.88 (d, J=1.6 Hz, 2H), 6.86-6.79 (m, 2H), 5.11 (d, J=2.8 Hz, 1H),3.79 (s, 3H); MS (ESI): m/z 391.0 [M+H]⁺.

Example 69 Compound 69,3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

A mixture of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (285 mg, 1.5 mmol),1,2-diphenylethanone (320 mg, 1.6 mmol), and urea (270 mg, 4.5 mmol) inanhydrous EtOH (5 mL) was added concentrated HCl solution (0.5 mL). Thereaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10:1) showed40% of the starting materials were consumed. The reaction mixture wasconcentrated, and purified by column chromatography (EtOAc:MeOH=40:1)and preparative HPLC to afford Compound 69 as a yellow solid (280 mg,yield: 45.7%). ¹H NMR (DMSO-d₆ 400 MHz TMS): δ 10.30 (s, 1H), 8.70 (d,J=1.2 Hz, 1H), 7.47 (s, 1H), 7.20-7.27 (m, 5H), 7.16 (d, J=1.6 Hz, 1H),6.98-7.06 (m, 4H), 6.80-6.82 (m, 2H), 5.14 (d, J=2.4 Hz, 1H), 4.00-4.10(m, 2H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 412.1 [M+1]⁺.

Example 70 Compound 70,2-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile

A mixture of 2-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 33) (100mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (87 mg, 0.41mmol), urea (81 mg, 1.36 mmol), and concentrated HCl solution (0.03 mL,0.41 mmol) in EtOH (5 mL) was refluxed overnight. The mixture wasconcentrated, and purified by preparative HPLC to give Compound 70(54.26 mg, yield 29%) as a yellow solid. ¹H NMR (DMSO-d₆ 300 MHz):δ10.24 (s, 1H), 8.91 (s, 1H), 7.61 (s, 1H), 7.51-7.44 (m, 2H), 7.31 (s,1H), 7.24-7.16 (m, 4H), 7.13-7.08 (m, 3H), 5.37 (s, 1H), 3.99-3.93 (m,2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 456.8 [M+1]⁺.

Example 71 Compound 71,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(pyridin-4-yl)ethanone (Intermediate 35) (60 mg,0.30 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (58 mg, 0.28 mmol),urea (50 mg, 0.83 mmol), and concentrated HCl solution (0.02 mL, 0.28mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporatedin vacuo and purified by preparative HPLC to give Compound 71 (55.17 mg,yield 46%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.29 (br, 1H), 8.92 (s, 1H),8.53 (d, J=5.6 Hz, 2H), 7.61 (s, 1H), 7.41 (d, J=1.6 Hz, 1H), 7.35 (d,J=1.6 Hz, 2H), 7.12-7.09 (m, 4H), 6.89 (d, J=7.6 Hz, 2H), 5.31 (d, J=2.8Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z433.0 [M+1]⁺.

Example 72 Compound 72,7-ethoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one

Step 1:

To a mixture of4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 1) (431 mg, 1.0 mmol) and NH₄Cl (268 mg, 5.0 mmol) inMeOH:THF:H₂O=2:1:1 (8 mL) was added iron power (280 mg, 5.0 mmol) andthe reaction mixture was heated to reflux for 1.0 h. The reactionmixture was cooled to room temperature and filtered. The filtered masswas washed with methanol (5.0 mL). The filtrate was concentrated invacuo to afford4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-oneas a white solid (386 mg, 96.3%), which was used directly for the nextstep.

Step 2:

To a solution of CDI (243 mg, 1.50 mmol) in THF (3 mL) was added4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(386 mg, 0.96 mmol) and the resultant mixture was heated to reflux for1.0 h. The reaction mixture was added water (10 mL) and filtered. Thefiltered mass was washed with methanol (3 mL) and dried to affordCompound 72 as a yellow solid (110 mg, 30%). ¹H NMR (DMSO-d₆ 500 MHz): δ11.56 (s, 1H), 8.69 (s, 1H), 7.49 (s, 1H), 7.21 (s, 3H), 7.20 (s, 2H),6.99-7.04 (m, 3H), 6.81 (d, J=6.0 Hz, 2H), 6.74 (d, J=6.0 Hz, 2H), 5.12(s, 1H), 4.11 (q, J=6.8 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H); MS (ESI): m/z428.1 [M+1]+.

Example 73 Compound 73,N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)acetamide

To a solution of compound6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 84) (100 mg, 0.22 mmol) in DCM (2 mL) was added Ac₂O (27 mg,0.27 mmol) at room temperature, and the mixture was stirred at roomtemperature for 4 hours. The mixture was evaporated in vacuo andpurified by column to give the Compound 73 (32.07 mg, yield 34%). ¹H NMR(DMSO-d₆ 300 MHz): δ 10.28 (brs, 1H), 9.95 (s, 1H), 8.66 (s, 1H), 7.52(s, 1H), 7.45-7.42 (m, 3H), 7.19 (d, J=1.8 Hz, 1H), 7.13-6.97 (m, 5H),6.83 (d, J=6.6 Hz, 2H), 5.17 (d, J=2.7 Hz, 1H), 4.10-4.01 (m, 2H), 2.02(s, 3H), 1.33 (t, J=6.9 Hz, 3H); MS (ESI): m/z 489.1 [M+1]⁺.

Example 74 Compound 74,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-phenyl-2-(pyridin-4-yl)ethanone (Intermediate 36) (100mg, 0.507 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (107 mg, 0.507mmol), urea (91.3 mg, 4.587 mmol), and concentrated hydrochloric acid(0.3 mL) in ethanol (1 mL) was refluxed at 79° C. for 80 h. After beingcooled down to room temperature, the mixture was evaporated, andpurified by preparative HPLC to give Compound 74 (80.1 mg, yield 38.3%).¹H NMR (DMSO-d₆ 400 MHz): δ 10.41 (s, 1H), 9.57 (s, 1H), 8.34 (d, J=6.4Hz, 2H), 8.02 (s, 1H), 7.50-7.42 (m, 4H), 7.39 (d, J=7.2 Hz, 2H), 7.34(d, J=1.6 Hz, 1H), 7.06 (d, J=6.4 Hz, 2H), 5.39 (d, J=3.2 Hz, 1H),4.15-4.10 (m, 2H), 1.38-1.35 (m, 3H); MS (ESI): m/z 433.0 [M+H]⁺.

Example 75 Compound 75,N-(3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 1) (400 mg, 0.93 mmol) was dissolved in an EtOH:H₂O:THF (8 mL,2:1:1) mixture. To this was added Zn dust (124 mg, 1.89 mmol) and NH₄Cl(104 mg, 1.94 mmol) and stirred at room temperature for 18 hours. Afterremoving a 1 mL aliquot of the reaction mixture, the remaining solutionwas filtered through a celite pad followed by a solvent swap to DCM/THF(2 mL/2 mL). Et₃N (0.1 mL, 0.72 mmol) was added and the solution wasstirred for 15 minutes. Mesyl chloride (40 μL, 0.24 mmol) was added andthe solution stirred at room temperature for 18 hours. Additional Et₃N(0.1 mL, 0.72 mmol) and mesyl chloride (30 μL, 0.18 mmol) was then addedand stirred for an additional 6 hours. The crude mixture wasconcentrated in vacuo and purified by silica-gel column chromatography(0-5% MeOH in EtOAc) to afford 25 mg of Compound 75 as a faint yellowsolid. ¹H NMR (CD₃OD 300 MHz): δ 7.25 (m, 5H), 7.16 (d, 1H), 7.03 (d,1H), 7.01 (d, 2H), 6.89 (m, 2H), 6.84 (d, 1H), 5.19 (s, 1H), 4.62 (s,1H), 4.10 (q, 2H), 2.87 (s, 3H), 1.40 (t, 3H); MS (ESI): m/z 480.23[M+1]⁺.

Example 76 Compound 76,N-(2-hydroxy-3-methoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide

4-(4-Hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 9) (100 mg, 0.24 mmol) was dissolved in an EtOH:H₂O:THF (4 mL,2:1:1) mixture. To this was added Zn dust (26 mg, 0.40 mmol) and NH₄Cl(26 mg, 0.48 mmol) and stirred at room temperature for 1 day, followedby stirring at 50° C. for 1 day. The solution was filtered through acelite pad followed by a solvent swap to DCM (5 mL). Excess Et₃N (0.1ml, 0.72 mmol) was added and stirred for 15 minutes, followed by excessaddition of mesyl chloride (50 μL, 0.3 mmol) and stirring over night.The crude mixture was directly purified by silica-gel columnchromatography (0 to 5% MeOH in EtOAc) to yield 10 mg of Compound 76 asa faint yellow solid. ¹H NMR (CD₃OD 300 MHz): δ 7.27 (m, 5H), 7.06 (m,1H), 7.04 (d, 2H), 6.91 (m, 2H), 6.61 (d, 1H), 6.38 (d, 1H), 5.51 (s,1H), 5.14 (s, 1H), 3.77 (s, 3H)); MS (ESI): m/z 466.17 [M+1]⁺.

Example 77 Compound 77,3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a mixture of 3-ethoxy-5-formyl-2-hydroxybenzoic acid (Intermediate37) (130 mg, 0.60 mmol), 1,2-diphenylethanone (150 mg, 0.76), and urea(80 mg, 1.3 mmol) in anhydrous EtOH (5 mL) was added concentrated HClsolution (0.2 mL), the reaction mixture was refluxed overnight. TLC(EtOAc:MeOH=10:1) showed about 50% of the starting materials wereconsumed. The reaction mixture was concentrated, and purified by columnchromatograph (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound77 as a yellow solid (15 mg, yield: 5.6%). ¹H NMR (DMSO-d₆ 400 MHz): δ11.37 (s, 1H), 8.66 (s, 1H), 7.47 (s, 1H), 7.43 (d, J=2.0 Hz, 1H),7.25-7.27 (m, 3H), 7.21-7.25 (m, 2H), 7.14 (d, J=2.0 Hz, 1H), 6.97-7.05(m, 3H), 6.81 (d, J=2.4 Hz, 2H), 5.10 (d, J=2.8 Hz, 1H), 3.97-4.02 (m,2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 431.1 [M+1]⁺.

Example 78 Compound 78,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(thiophen-2-yl)ethanone (Intermediate 38) (100mg, 0.49 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (95 mg, 0.45mmol), urea (81 mg, 1.35 mmol), and concentrated HCl solution (0.04 mL,0.45 mmol) in EtOH (5 mL) was refluxed overnight. The mixture wasdiluted with water, and extracted with EtOAc. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄, evaporated in vacuo, and purifiedby preparative HPLC to give Compound 78 (45 mg, yield 23%). ¹H NMR(DMSO-d₆ 300 MHz): δ 10.22 (s, 1H), 8.61 (s, 1H), 7.47 (s, 1H),7.34-7.29 (m, 2H), 7.15-7.13 (m, 1H), 7.09-7.06 (m, 3H), 6.99 (s, 1H),6.87-6.83 (m, 3H), 5.02 (d, J=2.4 Hz, 1H), 3.92 (q, J=7.2 Hz, 2H), 1.22(t, J=7.2 Hz, 3H); MS (ESI): m/z 438.0[M+1]⁺.

Example 79 Compound 79,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(thiophen-3-yl)ethanone (Intermediate 39) (100mg, 0.49 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (95 mg, 0.45mmol), urea (81 mg, 1.35 mmol), and concentrated HCl solution (0.04 mL,0.45 mmol) in EtOH (5 mL) was refluxed overnight. The mixture wasdiluted with water, and extracted with EtOAc. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄, evaporated in vacuo, and purifiedby preparative HPLC to give Compound 79 (45 mg, yield 23%). ¹H NMR(DMSO-d₆ 300 MHz): δ 10.19 (s, 1H), 8.50 (s, 1H), 7.43-7.40 (m, 2H),7.30-7.24 (m, 2H), 7.04-7.00 (m, 4H), 6.83-6.80 (m, 2H), 6.52 (s, J=5.1Hz, 1H), 5.07 (d, J=2.4 Hz, 1H), 3.97-3.88 (m, 2H), 1.22 (t, J=6.9 Hz,3H); MS (ESI): m/z 438.0 [M+1]⁺.

Example 80 Compound 80,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-imidazol-4-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(1-methyl-1H-imidazol-4-yl)-2-phenylethanone(Intermediate 40) (130 mg, 0.65 mmol), compound3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (165 mg, 0.78 mmol), and urea(117 mg, 1.95 mmol) in anhydrous EtOH (5 mL) was added concentrated HClsolution (0.2 mL), the reaction mixture was refluxed for 16 hours. Thereaction mixture was concentrated under reduced pressure, and purifiedby column chromatograph and preparative HPLC to afford Compound 80 as ayellow solid (87 mg, yield: 30.8%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.31(s, 1H), 8.62 (m, 2H), 7.68 (s, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.19-7.22(m, 3H), 7.06 (m, 2H), 6.97-7.00 (m, 2H), 5.25 (d, J=2.4 Hz, 1H),3.95-4.07 (m, 2H), 3.67 (s, 3H), 1.29-1.33 (t, J=6.8 Hz, 3H); MS (ESI):m/z 436.1 [M+1]⁺.

Example 81 Compound 81,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-1-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 1-(naphthalen-1-yl)-2-phenylethanone (Intermediate 41)(250 mg, 1.02 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (257.3 mg,1.22 mmol), and urea (182.9 mg, 3.05 mmol) in anhydrous EtOH (5 mL) wasadded concentrated HCl solution (0.2 mL), and the reaction mixture wasrefluxed for 14 hours. The reaction mixture was concentrated underreduced pressure, and purified by column chromatography and preparativeHPLC to afford Compound 81 as a yellow solid (89 mg, yield: 18.1%). ¹HNMR (DMSO-d₆ 400 MHz): δ 10.30 (s, 1H), 8.84 (s, 1H), 6.49-7.89 (m, 8H),6.87-7.23 (m, 7H), 5.26 (d, J=2.8 Hz, 1H), 4.02-4.11 (m, 2H), 1.32-1.36(t, J=6.8 Hz, 3H); MS (ESI): m/z 482.1 [M+1]⁺.

Example 82 Compound 82,3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide

A mixture of Compound 77 (described previously) (280 mg, 0.65 mmol),NH₄Cl (41 mg, 0.78 mmol), EDCI (149 mg, 0.78 mmol), HOBT (105 mg, 0.78mmol), and NMM (0.29 mL, 2.6 mmol) in DMF (5 mL) was stirred at roomtemperature for two hours. LCMS showed most of the starting material wasconsumed. 100 mL of a mixture of EtOAc and MeOH (v/v=10:1) was added todilute the mixture. The organic layer was washed with brine (20 mL×2),dried over Na₂SO₄, filtered, concentrated, and purified by preparativeHPLC to afford Compound 82 as a yellow solid (46 mg, yield: 16.4%). ¹HNMR (DMSO-d₆ 400 MHz): δ 12.94 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 7.86(s, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 7.20-7.25 (m, 5H), 7.11 (s, 1H),6.97-7.02 (m, 3H), 6.80 (d, J=6.8 Hz, 2H), 5.10 (d, J=2.4 Hz, 1H), 4.00(q, J=7.2 Hz, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 430.1 [M+1]⁺.

Example 83 Compound 83, methyl4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenylcarbamate

Step 1:

To a solution of6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 57) (100 mg, 0.224 mmol), and triethylamine (29.5 mg, 0.291mmol) in anhydrous dichloromethane (5 mL) was added methyl chloroformate(23.2 mg, 0.246 mmol) at 0° C. The mixture was stirred at 0° C. for 5 h.The reaction mixture was poured into water (10 mL), and the mixture wasextracted with dichloromethane (20 mL×2). The organic layers were washedwith brine (20 mL), dried over anhydrous sodium sulfate, and purified bypreparative HPLC to give methyl4-(6-(3-ethoxy-4-(methoxycarbonyloxy)-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenylcarbamate(60 mg, yield 47.6%)

Step 2:

To a mixture of the intermediate from Step 1 (60 mg, 0.107 mmol) inethanol (2 mL) was added sodium hydroxide aqueous solution (2 mL, 1.25mol/L) at 0° C., and the mixture was stirred at 28° C. for 4 h. Thereaction mixture was adjusted to pH=5 with diluted hydrochloric acid.The mixture was poured into water (20 mL), and extracted with ethylacetate (30 mL). The organic layer was washed with brine (50 mL), driedover anhydrous sodium sulfate, evaporated, and purified by preparativeHPLC to give Compound 83 (24.1 mg, yield 44.6%). ¹H NMR (DMSO-d₆400MHz): δ 10.28 (s, 1H), 9.70 (s, 1H), 8.64 (s, 1H), 7.51 (s, 1H), 7.44(s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.19 (s, 1H), 7.11 (d, J=8.4 Hz, 2H),7.07-7.00 (m, 3H), 6.84 (d, J=7.2 Hz, 2H), 5.16 (d, J=2.8 Hz, 1H),4.06-4.01 (m, 2H), 3.65 (s, 3H), 1.35-1.31 (m, 3H); MS (ESI): m/z 505.0[M+H]+.

Example 84 Compound 84,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-phenyl-2-(pyridin-3-yl)ethanone (Intermediate 42) (200mg, 1.01 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (213.3 mg, 1.01mmol), urea (181.8 mg, 3.03 mmol), and concentrated hydrochloric acidsolution (0.5 mL) in ethanol (2 mL) was refluxed at 78° C. for 70 h.After being cooled down to room temperature, the reaction mixture wasevaporated, and the residue was purified by preparative HPLC to giveCompound 84 (191.1 mg, yield 43.7%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.34(s, 1H), 9.06 (s, 1H), 8.35-8.33 (m, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.72(s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.33-7.23 (m, 6H),5.39 (d, J=2.8 Hz, 1H), 4.11-4.06 (m, 2H), 1.36-1.33 (m, 3H); MS (ESI):m/z 433.0 [M+H]⁺.

Example 85 Compound 85,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(naphthalen-2-yl)-2-phenylethanone (Intermediate 43) (260mg, 1.06 mmol), -ethoxy-4-hydroxy-5-nitrobenzaldehyde (267.6 mg, 1.27mmol), and urea (190.2 mg, 3.17 mmol) in anhydrous EtOH (5 mL) was addedconcentrated HCl solution (0.2 mL), and the reaction mixture wasrefluxed for 14 hours. The reaction mixture was concentrated underreduce pressure, and the residue was purified by column chromatography(EtOAc:MeOH=50:1) and preparative HPLC to afford Compound 85 as a yellowsolid (64 mg, yield: 12.6%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.12 (d,J=12.0 Hz, 1H), 8.65 (d, J=16.0 Hz, 1H), 7.67-7.81 (m, 3H), 7.30-7.46(m, 5H), 6.99-7.18 (m, 2H), 6.58-6.73 (m, 5H), 5.14-5.35 (m, 1H),3.90-3.96 (m, 2H), 1.16-1.22 (m, 3H); MS (ESI): m/z 482.1 [M+1]⁺.

Example 86 Compound 86,2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a mixture of 1,2-diphenylethanone (200 mg, 1.03 mmol),5-formyl-2-hydroxybenzoic acid (203 mg, 1.22 mmol), and urea (184 mg,3.06 mmol) in anhydrous EtOH was added concentrated HCl solution (105mg, 1.03 mmol). The reaction was refluxed for three days. The reactionmixture was concentrated, and purified by column chromatography andpreparative HPLC to give Compound 86 as an off-white solid (40 mg, yield10.2%). ¹H NMR (DMSO-d₆ 400 MHz): δ 11.20 (s, 1H), 8.63 (s, 1H), 7.78(d, J=2.4 Hz, 1H), 7.42-7.50 (m, 2H), 7.13-7.28 (m, 5H), 6.90-7.00 (m,4H), 6.75 (d, J=6.4 Hz, 2H), 5.10 (d, J=2.4 Hz, 1H); MS (ESI): m/z 387.1[M+1]⁺.

Example 87 Compound 87,4-(4-hydroxy-3-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1,2-diphenylethanone (392 mg, 2.0 mmol),4-hydroxy-3-methoxybenzaldehyde (274 mg, 1.8 mmol) and urea (324 mg, 5.4mmol) in EtOH (40 mL) was added concentrated HCl (0.17 mL). The mixturewas stirred at 85° C. for 3 days. The volatiles were removed underreduced pressure and the residue was diluted with water (50 mL),extracted with ethyl acetate (100 mL×2), washed with saturated aqueousNaHCO₃ (50 mL×2), dried over Na₂SO₄, concentrated (standardaqueous/EtOAc workup) and purified by silica gel column chromatography(PE:EA=1:1) to afford Compound 87 as an off-white power (100 mg, 15%).¹H NMR (DMSO-d₆ 500 MHz): δ 8.94 (s, 1H), 8.58 (s, 1H), 7.36 (s, 1H),7.53 (s, 1H), 7.40 (s, 3H), 7.34 (s, 3H), 7.10 (d, J=5.2 Hz, 1H),7.20-7.25 (m, 5H), 6.99 (t, J=18 Hz, 3H), 6.90 (s, 1H), 6.80 (t, J=7.0Hz, 3H), 6.74 (d, J=8.0 Hz, 1H), 4.99 (d, J=2.5 Hz, 1H); MS (ESI): m/z373.0 [M+1]⁺.

Example 88 Compound 88,5-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(4-(dimethylamino)phenyl)-1-phenylethanone(Intermediate 44) (235 mg, 1 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (212 mg, 1 mmol), and urea (138mg, 3 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HClsolution, and the mixture was stirred at 130° C. for 2 days. After thesolvent was removed under reduced pressure, the residue was purified bypreparative HPLC (40-80% acetonitrile+0.1% trifluoroacetic acid inwater, over 15 min.) to give the Compound 88 (65 mg, yield 13.9%). ¹HNMR (CD₃OD 400 MHz): δ 7.43 (s, 1H), 7.25-7.19 (m, 8H), 7.02 (d, J=8.4Hz, 2H), 5.30 (s, 1H), 4.06-4.00 (m, 2H), 3.06 (s, 6H), 1.33 (t, J=6.8Hz, 3H); MS (ESI): m/z 475.3 [M+1]⁺.

Example 89 Compound 89,4-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 8-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde(Intermediate 45) (110 mg, 0.529 mmol), 1,2-diphenylethanone (103.8 mg,0.529 mmol), urea (95.2 mg, 1.587 mmol), and concentrated hydrochloricacid (0.1 mL) in ethanol (10 mL) was refluxed at 77° C. for 63 h.Volatiles were removed, and purified by preparative HPLC to giveCompound 89 (12.1 mg, yield 5.5%). ¹H NMR (CD₃OD 400 MHZ): δ 7.32 (s,1H), 7.14 (s, 5H), 7.06 (s, 1H), 6.95-6.94 (m, 3H), 6.78-6.76 (m, 2H),5.20 (s, 1H), 4.26-4.24 (m, 4H); MS (ESI): m/z 430.0 [M+H]⁺.

Example 90 Compound 90,4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid

To a solution of 1,2-diphenylethanone (392 mg, 2.0 mmol),4-formylbenzoic acid (274 mg, 1.8 mmol) and urea (324 mg, 5.4 mmol) inEtOH (40 mL) was added concentrated HCl (0.17 mL). The mixture wasstirred at 85° C. for 3 days. The volatiles were removed under reducedpressure and standard aqueous/EtOAc workup procedure was followed.Purification by inverse-phase column to afford Compound 90 as a tanpowder (11 mg, 2%). ¹H NMR (MeOH-d₄ 500 MHz TMS): δ 7.99 (d, J=7.0 Hz,2H), 7.47 (d, J=7.0 Hz, 2H), 7.25 (s, 5H), 7.03 (s, 3H), 6.85 (s, 2H),5.40 (s, 1H); MS (ESI): m/z 371.0 [M+1]⁺.

Example 91 Compound 91,4-(3-(isoxazol-4-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1,2-diphenylethanone (46 mg, 0.233 mmol),3-(isoxazol-4-yl)benzaldehyde (Intermediate 46) (36 mg, 0.209 mmol) andurea (48 mg, 0.627 mmol) in EtOH (10 mL) was added concentrated HCl (0.4mL). The mixture was stirred at 85° C. for 14 h. The volatiles wereremoved under reduced pressure and the residue was purified by silicagel column chromatography (PE:EA=1:1) to afford Compound 91 as anoff-white power (18 mg, 22.2%). ¹H NMR (MeOH-d₄ 500 MHz): δ 8.99 (s,1H), 8.74 (s, 1H), 7.50-7.53 (m, 2H), 7.39-7.50 (m, 2H), 7.23-7.25 (m,5H), 7.00-7.02 (m, 2H), 6.84-6.87 (m, 2H), 5.35 (s, 1H); MS (ESI): m/z394.1 [M+1]⁺.

Example 92 Compound 92,1,1′-(2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-1,3-phenylene)diethanone

Step 1: Synthesis of4-(4-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1,2-diphenylethanone (1 g, 5.1 mmol), urea (1.22 g, 20.38mmol), 4-methoxybenzaldehyde (0.76 g, 1.1 mmol) and conc. HCl (0.4 mL)in EtOH (100 mL) was heated at 85° C. for 108 h. The volatiles wereremoved under reduced pressure and the residue was purified by columnchromatography to afford4-(4-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one as ayellow solid (400 mg, 22%)

Step 2: Synthesis of1,1′-(2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-1,3-phenylene)diethanone

Acetyl chloride (76 mg, 0.97 mmol) was added dropwise to the solution of4-(4-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (300 mg,0.84 mmol) in dry DCM (6 mL) at 0° C. Aluminum trichloride (393 mg, 1.15mmol) was then added. The mixture was stirred at room temperatureovernight. The mixture was poured into 1N HCl solution (15 mL) withice-bath and extracted with DCM (15 mL×3), the combined organic layerswere washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified twice by Prep-TLC(PE:EA=2:3) to afford Compound 92 (21 mg, 5.8%). MS (ESI): m/z 427.1[M+1]⁺.

Example 93 Compound 93,3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid

To a solution of 1,2-diphenylethanone (784 mg, 4.0 mmol),3-formylbenzoic acid (500 mg, 3.33 mmol) and urea (600 mg, 10.0 mmol) inEtOH (40 mL) was added concentrated HCl (1.6 mL). The mixture wasstirred at 85° C. for 3 days. The volatiles were removed under reducedpressure and standard aqueous/EtOAc workup procedure was followed.Purification by column chromatography (100% EA) gave Compound 93 as anoff-white powder (186 mg, 15%). ¹H NMR (DMSO-d₆ 500 MHz): δ 8.70 (s,1H), 7.99 (s, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.57 (s, 2H), 7.50 (t, J=14.5Hz, 1H), 7.21-7.25 (m, 5H), 6.79-7.02 (m, 3H), 6.78 (d, J=7.0 Hz, 2H),5.24 (d, J=2.0 Hz, 1H); MS (ESI): m/z 371.1 [M+1]⁺.

Example 94 Compound 94,2-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

To a solution of 1,2-diphenylethanone (1.6 g, 8.16 mmol), and3-formyl-2-hydroxybenzonitrile (Intermediate 47b) (1.0 g, 6.80 mmol) inAcOH (5 mL) was added urea (1.2 g, 20.4 mmol). The mixture was stirredat 120° C. under microwave for 3 h. The volatiles were removed underreduced pressure and standard aqueous workup procedure was followed. Thecrude was recrystallized by EA (10 mL) to afford Compound 94 as a whitepower (436 mg, 26%). ¹H NMR (DMSO-d₆500 MHz): δ 8.10 (s, 1H), 7.79 (d,J=2.5 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.58 (d, J=7.5 Hz, 3H), 7.30-7.36(m, 3H), 7.18 (s, 1H), 7.02 (d, J=6.0 Hz, 3H), 6.78 (d, J=6.0 Hz, 2H),4.44 (d, J=2.0 Hz, 1H), 4.14 (s, 1H); MS (ESI): m/z 368.1 [M+1]⁺.

Example 95 Compound 95,4-(4-hydroxy-3-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1,2-diphenylethanone (704 mg, 3.59 mmol),4-hydroxy-3-nitrobenzaldehyde (500 mg, 2.99 mmol) and urea (538 mg, 8.97mmol) in EtOH (40 mL) was added concentrated HCl (1.6 mL). The mixturewas stirred at 85° C. for 3 days. The volatiles were removed underreduced pressure and standard aqueous workup procedure was followed.Purification by silica gel column chromatography (PE:EA=1:1) gaveCompound 95 as an off-white power (102 mg, 9%). ¹H NMR (DMSO-d₆ 500 MHzTMS): δ 10.09 (s, 1H), 8.69 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.52-7.57(m, 2H), 7.21-7.26 (m, 5H), 7.13 (d, J=10.5 Hz, 1H), 7.01 (t, J=27.5 Hz,3H), 7.81 (d, J=8.5 Hz, 2H), 5.26 (d, J=3.5 Hz, 1H); MS (ESI): m/z 388.1[M+1]⁺

Example 96 Compound 96,2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

To a solution of 1,2-diphenylethanone (720 mg, 3.67 mmol),5-formyl-2-hydroxybenzonitrile (Intermediate 47a) (450 mg, 3.06 mmol)and urea (551 mg, 9.18 mmol) in EtOH (23 mL) was added concentrated HCl(0.9 mL). The mixture was stirred at 90° C. for 40 h. Followed standardaqueous workup procedure and recrystallized from EA (6 mL), then furtherpurified by prep-HPLC to afford Compound 96 as a white power (36 mg,3%). ¹H NMR (MeOH-d₄ 500 MHz): δ 7.50 (t, J=7.5 Hz, 1H), 7.42 (d, J=2.0Hz, 1H), 7.25 (s, 5H), 7.05 (t, J=2.5 Hz, 3H), 6.93 (d, J=8.5 Hz, 1H),6.85 (t, J=4.0 Hz, 2H), 5.30 (s, 1H); MS (ESI): m/z 368.1 [M+1]⁺.

Example 97 Compound 97,2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a solution of 1, 2-diphenylethanone (53 mg, 0.270 mmol), ethyl2-ethoxy-4-formylbenzoate (Intermediate 48) (50 mg, 0.225 mmol) and urea(41 mg, 0.675 mmol) in EtOH (2.5 mL) was added concentrated HCl (0.1mL). The mixture was stirred at 90° C. for 16 h. The volatiles wereremoved under reduced pressure to afford crude ethyl2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate,which was dissolved in THF/H₂O/MeOH (v/v/v=1/1/1, 0.6 mL) followed byaddition of lithium hydroxide monohydrate (14 mg, 0.338 mmol). Thesolution was stirred at room temperature overnight. Most of THF and MeOHwere evaporated under reduced pressure and the resulting aqueoussolution was acidified with 10% hydrochloric acid to pH=6.0. Theresulting precipitate was purified by prep-HPLC to afford Compound 97 asa white powder (11 mg, 12%). ¹H NMR (MeOH-d₄ 500 MHz): δ 7.68 (d, J=8.0Hz, 1H), 7.14 (s, 5H), 6.94-6.98 (m, 4H), 6.89 (s, 1H), 6.76 (t, J=3.5Hz, 2H), 5.26 (s, 1H), 3.90-4.00 (m, 2H), 1.27 (t, J=7.0 Hz, 3H); MS(ESI): m/z 415.1 [M+1]⁺.

Example 98 Compound 98,3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide

Prepared as a side product during the preparation of Compound 99.Isolated under same conditions as described for synthesis of Compound99, a white solid (6.7%). ¹H NMR (MeOH-d₄ 500 MHz): δ 7.90 (s, 1H), 7.78(d, J=7.5 Hz, 1H), 7.59 (d, J=7.0 Hz, 1H), 7.46 (t, J=3.0 Hz, 1H),7.25-7.27 (m, 5H), 7.01 (s, 3H), 6.85 (s, 2H), 5.41 (s, 1H); MS (ESI):m/z 370.1 [M+1]⁺.

Example 99 Compound 99,N-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzimidamide

Step 1: Synthesis of3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

To a mixture of 3-formylbenzonitrile (1.31 g, 10.0 mmol, 1.0 eq), 1,2-diphenylethaone (2.35 g, 12.0 mmol, 1.2 eq) and urea (1.8 g, 30.0mmol, 3.10 eq) in ethanol (100 mL) was added concentrated HCl (4 mL) andthe reaction solution was heated to reflux for 3 days. The reactionsolution was concentrated in vacuo and purified by silica gel columnchromatography (DCM:MeOH=20:1) to afford3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile as awhite solid (700 mg, 21%).

Step 2: Synthesis ofN-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzimidamide

A mixture of3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile (700mg, 2 mmol, 1 eq), NH₂OH—HCl (144 mg, 2.2 mmol, 1.1 eq) and Na₂CO₃ (414mg, 4.0 mmol, 2.0 eq) in methanol (5.0 mL) was heated to refluxovernight. The mixture was cooled to room temperature and filtered. Thefiltered mass was washed with methanol (5.0 mL) and purified byprep-HPLC to afford Compound 99 as a yellow solid (150 mg, 19.5%) andCompound 98 as a white solid (6.7%). Data for Compound 99: ¹H NMR(MeOH-d₄ 500 MHz TMS): δ 7.69-7.72 (m, 2H), 7.58-7.61 (m, 2H), 7.26 (br,5H), 7.04 (br, 2H), 6.88 (br, 2H), 5.51 (s 1H); MS (ESI): m/z 385.1.1[M+1]⁺.

Example 100 Compound 100,4-(3-bromo-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1,2-diphenylethanone (4.80 g, 25 mmol),3-bromo-5-ethoxy-4-hydroxybenzaldehyde (5.00 g, 20 mmol) and urea (3.68g, 61 mmol) in EtOH (250 mL) was added conc. HCl (10 mL). The mixturewas heated at reflux for 112 h. Followed standard aqueous workupprocedure and purified by silica gel column chromatography (PE:EA=1:3)to afford Compound 100 as a white solid (1.06 g, 11%). ¹H NMR (MeOH-d₄500 MHz TMS): δ 7.24 (s, 5H), 7.09 (s, 1H), 7.04 (s, 3H), 6.85 (s, 3H),5.17 (s, 1H), 4.03 (m, 2H), 1.37 (t, J=7.5 Hz, 3H); MS (ESI): m/z 465.0[M+1]⁺.

Example 101 Compound 101,N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide

Step 1: Synthesis of2-ethoxy-4-(6-(4-(methylsulfonamido)phenyl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenylmethanesulfonate

To a solution of6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one(Compound 57) (100 mg, 0.224 mmol) and triethylamine (29.5 mg, 0.291mmol) in anhydrous dichloromethane (3 mL) was added MsC1 (28 mg, 0.246mmol) at 0° C., and the mixture was stirred at 0° C. for 5 h. Thereaction mixture was poured into water (10 mL), and extracted withdichloromethane (20 mL). The organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, and purified by preparativeHPLC to give2-ethoxy-4-(6-(4-(methylsulfonamido)phenyl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenylmethanesulfonate (60 mg, yield 44.3%).

Step 2: Synthesis of Compound 101

To a mixture of2-ethoxy-4-(6-(4-(methylsulfonamido)phenyl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenylmethanesulfonate (60 mg, 0.10 mmol) in ethanol (2 mL) was added sodiumhydroxide aqueous solution (2 mL, 1.25 mol/L) at 0° C. The mixture washeated at 80° C. for 5 h, cooled down to room temperature, adjusted topH=5 with diluted hydrochloric acid, poured into water (20 mL), andextracted with ethyl acetate (30 mL). The organic layer was washed withbrine (5 mL), dried over anhydrous sodium sulfate, and evaporated. Theresidue was purified by preparative HPLC to give Compound 101 (36.0 mg,yield 68.9%). HNMR (DMSO-d₆ 300 MHz): δ 10.34 (s, 1H), 9.91 (s, 1H),8.73 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.23 (d, J=9.0 Hz, 3H),7.12-7.06 (m, 5H), 6.90 (d, J=6.9 Hz, 2H), 5.24 (d, J=2.7 Hz, 1H),4.12-4.08 (m, 2H), 3.04 (s, 3H), 1.42-1.37 (m, 3H); MS (ESI): m/z 525.0[M+H]⁺.

Example 102 Compound 102,4-(4-hydroxy-3-isopropoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

The mixture of 4-hydroxy-3-isopropoxy-5-nitrobenzaldehyde (Intermediate49) (116 mg, 0.516 mmol), 1,2-diphenylethanone (121 mg, 0.618 mmol),urea (93 mg, 1.55 mmol) and concentrated hydrochloric acid (0.1 mL) inanhydrous ethanol (5 mL) was stirred with reflux (110° C.) under N₂protection overnight. The reaction mixture was concentrated and theresidue was purified by silica gel column chromatography, followed bypreparative HPLC to give compound 102 (36.3 mg, yield 15.8%) as a solid.¹H NMR (DMSO-d₆ 400 MHz): δ 10.14 (s, 1H), 8.72 (s, 1H), 6.82-7.55 (m,13H), 5.21 (d, J=2.8 Hz, 1H), 4.47-4.53 (m, 1H), 1.28 (d, J=6.0 Hz, 3H),1.25 (d, J=6.0 Hz, 3H); MS (ESI): m/z 446.1 [M+1]⁺.

Example 103 Compound 103,4-(3-ethoxy-4-hydroxy-5-(methylsulfonyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

Step 1: Synthesis of4-(3-ethoxy-4-hydroxy-5-(methylthio)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 3-ethoxy-4-hydroxy-5-(methylthio)benzaldehyde(Intermediate 50) (300 mg, 1.42 mmol), 1,2-diphenylethanone (330 mg,1.68 mmol) and urea (170 mg, 2.80 mmol) in ethanol (5 mL) was addedconc. HCl (0.3 mL) and the reaction mixture was refluxed under N₂atmosphere overnight. The resulting mixture was cooled and purified bysilica gel column to give desired product (200 mg, yield 33%).

Step 2: Synthesis of Compound 103

To the solution of4-(3-ethoxy-4-hydroxy-5-(methylthio)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one(200 mg, 0.46 mmol) in DCM (10 mL) was added m-CPBA (112 mg, 0.55 mmol)at 0° C., the mixture was stirred over 2 hours at 0° C. The reactionsolution was washed with Na₂SO₃ solution, and brine, then concentratedunder reduced pressure. The residue was purified by prep-HPLC (0.1% TFAas additive) to give Compound 103 (24.5 mg, yield 11%) and Compound 104(40 mg, yield 19%). Data for Compound 103: ¹H NMR (400 MHz, DMSO-d₆): δ10.18 (s, 1H), 8.70 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.27-7.21 (m,6H), 7.03-6.99 (m, 3H), 6.80 (d, J=6.8 Hz, 2H), 5.13 (d, J=2.8 Hz, 1H),4.10-4.00 (m, 2H), 3.23 (s, 3H), 1.34 (t, J=6.8 Hz, 3H) MS (ESI): m/z465.3 [M+1]⁺.

Example 104 Compound 104,4-(3-ethoxy-4-hydroxy-5-(methylsulfinyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

See procedure described for Compound 103 in Example 103. Data forCompound 104: ¹H NMR (300 MHz, DMSO-d₆): δ 9.66 (s, 1H), 8.65 (s, 1H),7.450-7.40 (m, 1H), 7.29-7.10 (m, 6H), 7.10-6.99 (m, 4H), 6.82-6.77 (m,2H), 5.14 (s, 1H), 4.10-3.98 (m, 2H), 2.65 (d, J=7.2 Hz, 3H), 1.33 (t,J=7.2 Hz, 3H) MS (ESI): m/z 449.2 [M+1]⁺

Example 105 Compound 105,3-ethoxy-2-hydroxy-5-(2-oxo-6-phenyl-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

To a solution of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (Intermediate51) (70 mg, 0.37 mmol), 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate2) (50 mg, 0.28 mmol) and urea (71 mg, 1.1 mmol) in 3 mL of ethanol wasadded 0.2 mL of concentrated HCl. Refluxed for 2 days. Solvent removedand resulting residue was purified by prep-HPLC (0.1% TFA as additive)to give Compound 105 (18 mg, yield 12%). ¹H NMR (DMSO-d₆ 300 MHz): δ10.33 (s, 1H), 8.70 (s, 1H), 7.51 (s, 1H), 7.37-7.10 (m, 8H), 6.84 (s,1H), 6.22 (d, J=4.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.07 (q, J=6.9 Hz,2H), 1.35 (t, J=6.9 Hz, 3H). MS (ESI): m/z 418.0 [M+1]⁺.

Example 106 Compound 106,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of Compound 107 (100 mg, 0.18 mmol) and NaOH aqueous solution(2 mL, 4M) in methanol (5 mL) was stirred at room temperature for 1hour. The mixture was diluted with water, extracted with EtOAc, driedover Na₂SO₄, concentrated in vacuo, and purified by columnchromatography (PE:EtOAc=1:3) to afford the Compound 106 (50 mg, yield66.7%). ¹H NMR (CD₃OD 300 MHz): δ 7.42 (d, J=1.8 Hz, 1H), 7.06-7.01 (m,4H), 6.90-6.88 (m, 2H), 6.49-6.46 (m, 2H), 5.70 (d, J=1.8 Hz, 1H), 5.06(s, 1H), 3.95-3.90 (m, 2H), 1.28 (t, J=6.9 Hz, 3H); MS (ESI): m/z 421.2[M+1]⁺.

Example 107 Compound 107,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-phenyl-1-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethanone(Intermediate 52) (200 mg, 0.6 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (130 mg, 0.6 mmol), and urea (108mg, 1.8 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HClsolution. The mixture refluxed overnight, concentrated in vacuo, andpurified by TLC (PE:EtOAc=1:2) to afford the Compound 107 (95 mg, yield27.6%). ¹H NMR (DMSO-d₆ 400 MHz): δ10.25 (s, 1H), 8.53 (s, 1H), 7.86 (d,J=7.6 Hz, 2H), 7.77 (t, J=7.6 Hz, 1H), 7.65 (t, J=8.0 Hz, 2H), 7.49 (s,1H), 7.36 (s, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.17-7.14 (m, 3H), 7.12 (t,J=2.8 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.91-6.89 (m, 2H), 5.70 (m, 1H),5.10 (d, J=2.4 Hz, 1H), 4.05-3.90 (m, 2H), 1.29 (t, J=7.2 Hz, 3H); MS(ESI): m/z 561.3 [M+1]⁺.

Example 108 Compound 108,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-fluorophenyl)-2-(3-methoxyphenyl)ethanone(Intermediate 53) (200 mg, 0.82 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (157 mg, 0.74 mmol), urea (134mg, 2.23 mmol), concentrated HCl (0.06 mL, 0.74 mmol) in EtOH (5 mL) wasrefluxed overnight. Followed standard aqueous/EtOAc workup procedure,then purified by preparative HPLC to give Compound 108 (70 mg, yield20%). ¹H NMR (DMSO-d₆ 300 MHz): δ 10.29 (s, 1H), 8.77 (s, 1H), 7.55 (s,1H), 7.45 (s, 1H), 7.27-7.24 (m, 2H), 7.20 (s, 1H), 7.15-7.09 (m, 2H),6.99-6.94 (m, 1H), 6.59 (d, J=7.2 Hz, 1H), 6.39 (d, J=6.3 Hz, 2H), 5.22(s, 1H), 4.07-4.05 (m, 2H), 3.49 (s, 3H), 1.33 (t, J=6.6 Hz, 3H); MS(ESI): m/z 479.9 [M+1]⁺.

Example 109 Compound 109,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(4-fluorophenyl)-2-(thiophen-3-yl)ethanone (Intermediate54) (100 mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (87 mg,0.41 mmol), urea (74 mg, 1.24 mmol), concentrated HCl (0.04 mL, 0.41mmol) in EtOH (5 mL) was refluxed overnight. Followed standardaqueous/EtOAc workup procedure, then purified by preparative HPLC togive Compound 109 (50 mg, yield 27%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30(s, 1H), 8.77 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.34-7.30 (m, 2H),7.27 (s, 1H), 7.23-7.18 (m, 3H), 6.88 (s, 1H), 6.27 (d, J=5.2 Hz, 1H),5.21 (d, J=2.8 Hz, 1H), 4.13-4.06 (m, 2H), 1.36 (t, J=6.8 Hz, 3H); MS(ESI): m/z 456.0 [M+1]⁺.

Example 110 Compound 110,2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 5-formyl-2-hydroxy-3-nitrobenzoic acid (Intermediate 55)(200 mg, 0.95 mmol), 1,2-diphenylethanone (185.8 mg, 0.95 mmol), urea(170.5 mg, 2.84 mmol), concentrated hydrochloric acid solution (0.3 mL)in ethanol (2 mL) was refluxed at 78° C. for 33 h. The reaction mixturewas evaporated in vacuo, and purified by preparative HPLC to giveCompound 110 (75.7 mg, yield 18.5%). ¹H NMR (DMSO-D₆, 400 MHZ): δ 8.78(s, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.60 (s, 1H),7.26-7.19 (m, 5H), 7.04-6.99 (m, 3H), 6.81 (d, J=6.4 Hz, 2H), 5.27 (d,J=2.8 Hz, 1H); MS (ESI): m/z 432.1 [M+H]⁺.

Example 111 Compound 111,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(furan-2-yl)-2-phenylethanone (commercially available)(420 mg, 2.26 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (433 mg,2.05 mmol), urea (369 mg, 6.15 mmol), concentrated HCl (0.2 mL, 2.05mmol) in EtOH (5 mL) was refluxed overnight. Followed standardaqueous/EtOAc workup procedure, then purified by preparative HPLC togive Compound 111 (83 mg, yield 9%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.32(s, 1H), 8.63 (s, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.37 (d, J=1.6 Hz,1H), 7.21-7.18 (m, 3H), 7.10 (d, J=1.2 Hz, 1H), 6.93-6.91 (m, 2H), 6.43(d, J=3.2 Hz, 1H), 6.29 (d, J=3.2 Hz, 1H), 5.12 (d, J=2.8 Hz, 1H),4.06-3.96 (m, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 422.0 [M+1]⁺.

Example 112 Compound 112,2-ethoxy-4-(2-imino-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol

A mixture of 1,2-diphenylethanone (500 mg, 2.55 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (538.5 mg, 2.55 mmol), guanidinehydrochloride (731 mg, 7.65 mmol), diisopropylamine (1.1 mL) in ethanol(5 mL) was refluxed at 80° C. for 60 h. The mixture was evaporated underreduced pressure and the residue was treated with a mixture of saturatedaqueous sodium bisulfite solution (50 mL), dichloromethane (100 mL) andisopropanol (30 mL), and the resulting mixture was stirred at roomtemperature for 30 min. The organic layer was separated and the aqueouslayer was extracted with a mixture of dichloromethane and isopropanol(3:1, 50 mL×2). The combined organic layer was dried over anhydroussodium sulfate and purified by preparative HPLC. The product containingfractions were treated with HCl/MeOH (2 mL, 2 N) and concentrated invacuo to give Compound 112 as an HCl salt (280 mg, yield 25.45%). ¹H NMR(DMSO-d₆ 400 MHZ): δ 10.48 (s, 1H), 10.27 (s, 1H), 9.35 (s, 1H), 7.59(s, 2H), 7.53 (s, 1H), 7.52-7.31 (m, 5H), 7.26 (d, J=2.0 Hz, 1H),7.12-7.10 (m, 3H), 6.92-6.90 (m, 2H), 5.57 (d, J=3.2 Hz, 1H), 4.1-4.06(q, J=7.2 Hz, 2H), 1.36-1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 431.0[M+H]⁺.

Example 113 Compound 113,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(4-(trifluoromethyl)phenyl)ethanone(commercially available) (200 mg, 0.76 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (145 mg, 0.69 mmol), urea (124mg, 2.06 mmol), conc. HCl (0.06 mL, 0.69 mmol) in EtOH (5 mL) wasrefluxed overnight. Followed a standard aqueous/EtOAc workup, thenpurified by preparative HPLC to give Compound 113 (135.34 mg, yield39%). ¹H NMR (DMSO-d₆400 MHz): δ 8.83 (d, J=1.6 Hz, 1H), 7.60-7.56 (m,3H), 7.40-7.39 (m, 3H), 7.13 (s, 1H), 7.06-7.00 (m, 3H), 6.83-6.80 (m,2H), 5.23 (d, J=2.4 Hz, 1H), 4.06-3.97 (m, 2H), 1.30 (t, J=7.2 Hz, 3H);MS (ESI): m/z 500.0 [M+1]⁺.

Example 114 Compound 114,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-o-tolyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-o-tolylethanone (commercially available) (200mg, 0.95 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (183 mg, 0.86mmol), urea (156 mg, 2.59 mmol), concentrated HCl (0.07 mL, 0.86 mmol)in EtOH (5 mL) was refluxed overnight. Followed standard aqueous/EtOAcworkup, then purified by preparative HPLC to give Compound 114 (31.75mg, yield 8%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.33 (br, 1H), 8.59 (s, 1H),7.51-7.44 (m, 2H), 7.23-7.13 (m, 4H), 6.96-6.89 (m, 4H), 6.80-6.77 (m,2H), 5.36-5.21 (m, 1H), 4.08-3.99 (m, 2H), 2.36 (s, 1.6H), 2.13 (s,1.3H), 1.34-1.28 (m, 3H); MS (ESI): m/z 446.0 [M+1]⁺.

Example 115 Compound 115,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-(3-fluorophenyl)-1-phenylethanone (commerciallyavailable) (200 mg, 0.93 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde(197 mg, 0.93 mmol), urea (168 mg, 2.8 mmol), conc. hydrochloric acid(0.5 mL) in ethanol (3 mL) was refluxed for 61 hours. After cooling toroom temperature, the mixture was evaporated and purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate=3:1) to giveCompound 115 (85.8 mg, yield 20%). HNMR (DMSO-d₆ 400 MHZ): δ 10.31 (brs,1H), 8.82 (s, 1H), 7.59 (s, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.31-7.22 (m,6H), 7.10-7.00 (m, 1H), 6.84-6.80 (m, 1H), 6.64-6.56 (m, 2H), 5.26 (d,J=2.4 Hz, 1H), 4.15-4.00 (m, 2H), 1.36 (t, J=6.8 Hz, 3H). MS (ESI): m/z450.0 [M+H]⁺.

Example 116 Compound 116,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate56) (100 mg, 0.492 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (94 mg,0.45 mmol), urea (81 mg, 1.34 mmol), concentrated HCl (0.04 mL, 0.45mmol) in EtOH (5 mL) was refluxed overnight. Then the mixture wasevaporated in vacuo and the residue was purified by preparative HPLC togive Compound 116 (65 mg, yield 33%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.30(s, 1H), 8.92 (s, 1H), 8.56-8.54 (m, 1H), 8.46-8.44 (m, 1H), 7.77 (d,J=8.0 Hz, 1H), 7.63 (s, 1H), 7.48-7.43 (m, 2H), 7.25-7.22 (m, 2H), 6.94(s, 1H), 6.35 (d, J=5.2 Hz, 1H), 5.27 (d, J=2.8 Hz, 1H), 4.12-4.04 (m,2H), 1.35 (t, J=6.8 Hz, 3H); MS (ESI): 438.9 m/z [M+1]⁺.

Example 117 Compound 117,(Z)-2-ethoxy-4-(2-(methylimino)-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol

A mixture of crude4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione(Compound 8) (392 mg, 0.877 mmol), m-CPBA (887 mg of 85% purity, 4.38mmol) and aqueous methylamine solution (3 mL) in ethanol (20 mL) wasstirred at 0° C. for 2 h, then at room temperature overnight. Na₂SO₃ (2g) was added and then dilute hydrochloride acid was added drop wise toadjust the pH to about 6. The above mixture was extracted with ethylacetate (40 mL×3), dried over Na₂SO₄, filtered, concentrated andpurified by silica gel column chromatography, followed by preparativeHPLC twice to afford Compound 117 (26 mg, yield: 6.7%). ¹H NMR (DMSO-d₆400 MHz): δ 8.73 (s, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.53 (s, 1H), 7.48 (s,2H), 7.33 (s, 4H), 7.10-7.11 (m, 3H), 7.01 (s, 1H), 6.89-6.91 (m, 3H),5.22 (s, 1H), 3.93 (d, J=6.8 Hz, 1H), 2.78 (s, 3H), 1.24-1.27 (t, J=4.8Hz, 3H); MS (ESI): m/z 445.2[M+1]⁺.

Example 118 Compound 118,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone(Intermediate 57) (160 mg, 0.78 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (164 mg, 0.78 mmol) and urea (110mg, 2.4 mmol) in 15 mL of ethanol was added 0.2 mL of conc. HCl, and themixture was stirred at reflux overnight. The mixture was cooled to roomtemperature and filtered. The solid was washed with ethanol and dried invacuo to give Compound 118 as an HCl salt (49 mg, yield 14.3%). ¹H NMR(DMSO-d₆ 400 MHz): δ 10.26 (s, 1H), 8.45 (s, 1H), 7.61 (s, 1H), 7.48 (s,1H), 7.38 (d, J=4.8 Hz, 1H), 7.38 (s, 1H), 7.09 (d, J=1.6 Hz, 1H), 7.04(s, 2H), 6.62 (d, J=5.2 Hz, 1H), 5.07 (d, J=2.4 Hz, 1H), 4.05-4.05 (m,2H), 3.75 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 442.2 [M+1]⁺.

Example 119 Compound 119,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(1-methyl-1H-pyrazol-3-yl)-2-(thiophen-3-yl)ethanone(Intermediate 58) (750 mg, 3.6 mmol),4-hydroxy-3-methoxy-5-nitrobenzaldehyde (782 mg, 3.7 mmol), urea (666mg, 11.1 mmol) and conc. HCl (0.2 mL) in EtOH (10 mL) was refluxedovernight. The mixture was concentrated under reduced pressure todryness and purified by prep-HPLC (0.1% TFA as additive) to giveCompound 119 (1.3 g, yield 81%). ¹H NMR and MS (ESI) characterizationincluded for the individual enantiomers, see Compound 149 and Compound150.

Example 120 Compound 120,4-(3-chloro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 3-chloro-4-hydroxy-5-nitrobenzaldehyde (Intermediate 59)(150 mg, 0.74 mmol), 1,2-diphenylethanone (146.0 mg, 0.74 mmol), urea(133.9 mg, 2.23 mmol), concentrated hydrochloric acid (0.5 mL) inethanol (3 mL) was refluxed at 78° C. for 45 h. After cooling, themixture was evaporated and the residue was purified by preparative HPLCto give Compound 120 (129.1 mg, yield 41.4%). HNMR (DMSO-d₆ 400 MHz): δ11.09 (s, 1H), 8.79 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz,1H), 7.59 (s, 1H), 7.27-7.21 (m, 5H), 7.05-7.00 (m, 3H), 6.83-6.81 (m,2H), 5.28 (d, J=2.8 Hz, 1H); MS (ESI): m/z 422.0 [M+H]⁺.

Example 121 Compound 121,6-(3-chloro-5-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3-chloro-5-fluorophenyl)-2-phenylethanone (Intermediate60) (150 mg, 0.60 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (116 mg,0.55 mmol), urea (99 mg, 1.65 mmol), concentrated HCl (0.05 mL, 0.55mmol) in EtOH (5 mL) was refluxed overnight. Followed standardaqueous/EtOAc workup and purified by preparative HPLC to give Compound121 (155 mg, yield 58%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.27 (brs, 1H),8.85 (s, 1H), 7.58 (s, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.34 (d, J=8.8 Hz,1H), 7.25 (s, 1H), 7.12 (d, J=6.4 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 7.01(d, J=7.2 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 5.27 (d, J=2.4 Hz, 1H),4.09-3.99 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 484.1 [M+1]⁺.

Example 122 Compound 122,2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

A mixture of 5-formyl-2-hydroxy-3-nitrobenzonitrile (Intermediate 61)(150 mg, 0.78 mmol), 1,2-diphenylethanone (153 mg, 0.78 mmol), urea (141mg, 2.34 mmol), conc. hydrochloric acid (0.5 mL) in ethanol (3 mL) wasrefluxed for 37 hours. The mixture was evaporated and purified by prep.HPLC (0.1% TFA as additive) to give Compound 122 (51 mg, yield 16%).HNMR (DMSO-d₆, 400 MHz): δ 8.77 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.92(d, J=2.4 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.25-7.21 (m, 5H), 7.01-6.98(m, 3H), 6.82-6.79 (m, 2H), 5.31 (d, J=2.8 Hz, 1H), MS (ESI): m/z 413.0[M+H]⁺.

Example 123 Compound 123,2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonicacid

Step 1: Synthesis of4-(4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

Followed the procedure described in Example 86, starting from4-hydroxybenzaldehyde, 1,2-diphenylethanone and urea, and acetic acidwas used instead of HCl.

Step 2: Synthesis of2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonicacid

To a solution of4-(4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (68 mg,0.2 mmol) in CHCl₃ (1 mL) was added ClSO₃H (35 mg, 0.3 mmol). Themixture was heated to 50° C. overnight. The residue was purified byprep-HPLC to give Compound 123 as a white power (6 mg, 7%). ¹H NMR(MeOH-d₄ 500 MHz): δ 7.75 (d, J=7.5 Hz, 1H), 7.38 (d, J=7 Hz, 1H), 7.30(m, 2H), 7.24 (t, J=1, 5 Hz, 3H), 7.01 (t, J=3.5, 5 Hz, 3H), 6.87 (m,3H), 5.23 (s, 1H); MS (ESI): m/z 423.0 [M+1]⁺.

Example 124 Compound 124,(R)-3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

Single enantiomer of Compound 126 (see Example 126 for synthesis). Thetwo enantiomers were separated by chiral supercritical chromatography(SFC separation condition: Column: AS-20 UM, 300*300 mm, 20 UM; MobilePhase: Supercritical Fluid CO2:MeOH=70:30, 80 ML/MIN; DetectorWavelength: 220 nm), the eluting solution for the first peak wascollected and evaporated to give one enantiomer as Compound 124 (29.29mg, yield 4%). ¹H NMR (DMSO-d₆ 400 MHz): δ 11.38 (br, 1H), 8.90 (s, 1H),8.59 (d, J=6.0 Hz, 1H), 8.49 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.58-7.52(m, 2H), 7.44 (d, J=2.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.16 (d, J=2.0 Hz,1H), 6.90-6.89 (m, 1H), 6.35 (dd, J=0.8 Hz, J=4.8 Hz, 1H), 5.19 (d,J=2.0 Hz, 1H), 4.05-3.96 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z438.0 [M+1]⁺; [α]²⁰ _(D)=0.403 (c=8.9 mg/mL, MeOH).

Example 125 Compound 125,(S)-3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

Single enantiomer of Compound 126 (see Example 126 for synthesis). Thetwo enantiomers were separated by chiral supercritical chromatography(see Example 124 for conditions). The eluting solution for the secondpeak was collected and evaporated to give another enantiomer as Compound125 (13.09 mg, yield 2%). ¹H NMR (DMSO-d₆ 400 MHz): δ 11.35 (br, 1H),8.87 (d, J=1.6 Hz, 1H), 8.56 (dd, J=1.6 Hz, J=5.2 Hz, 1H), 8.45 (d,J=1.6 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.51-7.48 (m, 1H),7.42 (d, J=2.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.87(dd, J=1.2 Hz, J=3.2 Hz, 1H), 6.33 (dd, J=1.2 Hz, J=4.8 Hz, 1H), 5.16(d, J=2.8 Hz, 1H), 4.03-3.95 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); m/z 438.0[M+1]⁺; [α]²⁰ _(D)=−0.398 (c=11.3 mg/mL, MeOH).

Example 126 Compound 126,3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate56) (372 mg, 1.83 mmol), 3-ethoxy-5-formyl-2-hydroxybenzoic acid(Intermediate 62) (350 mg, 1.67 mmol), urea (300 mg, 5.00 mmol) and HCl(12 M, 0.14 mL, 1.67 mmol) in EtOH (10 mL) was refluxed overnight. Themixture was concentrated in vacuo and purified by preparative HPLC togive Compound 126 (240 mg, yield 33%) as a yellow solid. ¹H NMR (DMSO-d₆400 MHz): δ 11.35 (br, 1H), 8.87 (d, J=1.6 Hz, 1H), 8.56 (dd, J=1.6 Hz,J=5.2 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.56 (s,1H), 7.51-7.48 (m, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.15(d, J=2.0 Hz, 1H), 6.87 (dd, J=1.2 Hz, J=3.2 Hz, 1H), 6.33 (dd, J=1.2Hz, J=4.8 Hz, 1H), 5.16 (d, J=2.4 Hz, 1H), 4.03-3.95 (m, 2H), 1.31 (t,J=6.8 Hz, 3H); MS (ESI): m/z 438.0 [M+1]⁺;

Example 127 Compound 127,4-(3-fluoro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 3-fluoro-4-hydroxy-5-nitrobenzaldehyde (Intermediate 63)(150 mg, 0.81 mmol), 1,2-diphenylethanone (159 mg, 0.81 mmol), urea (145mg, 2.43 mmol), concentrated hydrochloric acid (0.5 mL) in ethanol (2mL) was refluxed at 86° C. for 46 hours. After cooling, the mixture wasevaporated and the crude product was purified by preparative HPLC togive Compound 127 (136.1 mg, yield 41.4%). HNMR (DMSO-d₆ 400 MHz): δ11.25 (s, 1H), 8.77 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.52-7.49 (m,1H), 7.27-7.22 (m, 5H), 7.06-6.98 (m, 3H), 6.83 (d, J=6.4 Hz, 2H), 5.27(d, J=2.4 Hz, 1H); MS (ESI): m/z 406.0 [M+H]⁺.

Example 128 Compound 128,3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile

To a solution of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone(Intermediate 56) (100 mg, 0.50 mmol),3-ethoxy-5-formyl-2-hydroxy-benzonitrile (Intermediate 51) (95.6 mg,0.50 mmol) and urea (150 mg, 2.50 mmol) in 3 mL of ethanol was added 0.2mL of concentrated HCl, and the mixture was refluxed for 2 days. Afterthe solvent was removed under reduced pressure, the residue was purifiedby reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give compound 128 (110 mg, yield 53.5%). ¹H NMR (DMSO-d₆ 400 MHz) δ8.99 (s, 1H), 8.74 (s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.77 (m, 1H), 7.63(s, 1H), 7.28 (m, 2H), 7.17 (m, 3H), 6.98 (d, J=2.4 Hz, 1H), 6.46 (d,J=4.8 Hz, 1H), 5.27 (d, J=6.4 Hz, 1H), 4.07 (m, 2H); 1.34 (t, J=7.2 Hz,3H); MS (ESI): m/z 419.2 [M+1]⁺.

Example 129 Compound 129,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(3-hydroxyphenyl)-2-phenylethanone (Intermediate 64) (154mg, 0.726 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (153.3 mg, 0.726mmol), urea (130.7 mg, 2.178 mmol), concentrated hydrochloric acid (0.5mL) in ethanol (2 mL) was refluxed at 79° C. for 50 h. Removed solventand purified by preparative HPLC to give Compound 129 (110 mg, yield33.9%). HNMR (DMSO-d₆ 400 MHz): δ 10.29 (s, 1H), 9.41 (s, 1H), 8.62 (d,J=1.6 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.19 (d, J=2.0 Hz,1H), 7.05-6.97 (m, 4H), 6.83-6.80 (m, 2H), 6.65-6.58 (m, 3H), 5.12 (d,J=2.8 Hz, 1H), 4.05-4.02 (m, 2H), 1.34-1.30 (m, 3H); MS (ESI): m/z 448.0[M+H]⁺.

Example 130 Compound 130,4-(4-hydroxy-3-nitro-5-propoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

The mixture of 4-hydroxy-3-nitro-5-propoxybenzaldehyde (Intermediate 65)(126 mg, 0.56 mmol), 1,2-diphenylethanone (131 mg, 0.672 mmol), urea(100 mg, 1.68 mmol) and concentrated hydrochloric acid (0.1 mL) inethanol (5 mL) was stirred at reflux (110° C.) under N₂ overnight. Thereaction was concentrated and purified by silica gel columnchromatography, followed by preparative HPLC to give Compound 130 (27mg, yield 10.8%) as a solid. ¹H NMR (DMSO-d₆ 400 MHz): δ 10.27 (s, 1H),8.72 (d, J=1.6 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.18-7.27(m, 6H), 7.00-7.06 (m, 3H), 6.82-6.84 (m, 2H), 5.197 (d, J=2.8 Hz, 1H),3.90-3.97 (m, 2H), 1.71-1.76 (m, 2H), 0.970 (t, J=7.6 Hz, 3H); MS (ESI):m/z 446.3 [M+1]⁺.

Example 131 Compound 131,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyrazin-2-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(pyrazin-2-yl)-2-(thiophen-3-yl)ethanone(Intermediate 66) (30 mg, 0.15 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (31 mg, 0.15 mmol) and urea (27mg, 0.45 mmol) in 2 mL of ethanol was added 0.2 mL of conc. HCl, and wasstirred at reflux overnight. The mixture was cooled and then purified bypreparative HPLC (30-60% acetonitrile+0.15% trifluoroacetic acid inwater, over 15 min.), the desired eluting solution was treated withHCl/MeOH (2 mL, 2M) and concentrated in vacuo to give Compound 131 asHCl salt (8.3 mg, yield 12.3%). ¹H NMR (CD₃OD 400 MHz): δ 8.69 (dd,J=1.6 Hz, 2.4 Hz, 1H), 8.48 (d, J=3.6 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H),7.60 (d, J=2.0 Hz, 1H), 7.37 (dd, J=3.2 Hz, 5.2 Hz, 1H), 7.18 (d, J=2.0Hz, 1H), 7.02 (dd, J=1.2 Hz, 2.8 Hz, 1H), 6.66 (dd, J=1.2 Hz, 5.2 Hz,1H), 5.42 (s, 1H), 4.11-4.06 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); MS (ESI):m/z 440.2 [M+1]⁺.

Example 132 Compound 132,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(quinolin-6-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-phenyl-1-(quinolin-6-yl)ethanone (Intermediate 67)(100 mg, 0.4 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (85 mg, 0.4mmol) and urea (72 mg, 1.2 mmol) in 2 mL of ethanol was added 0.5 mL ofconc. HCl and was stirred at reflux overnight. The mixture was cooled toroom temperature and purified by preparative HPLC (20-50%acetonitrile+0.15% trifluoroacetic acid in water, over 15 min.),followed by column chromatography (PE:EtOAc=2:1-EtOAc:MeOH=10:1) to giveCompound 132 (18 mg, yield 11.8%). ¹H NMR (CD₃OD 400 MHz): δ 8.84 (d,J=3.2 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J=8.8 Hz,1H), 7.66 (s, 1H), 7.59-7.52 (m, 2H), 7.19 (s, 1H), 7.06 (m, 3H),6.95-6.94 (m, 2H), 5.45 (s, 1H), 4.13-4.05 (m, 2H), 1.41 (t, J=6.8 Hz,3H); MS (ESI): m/z 483.3 [M+1]⁺.

Example 133 Compound 133,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(isoquinolin-6-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 1-(isoquinolin-6-yl)-2-phenylethanone (Intermediate 68)(100 mg, 0.4 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (85 mg, 0.4mmol) and urea (72 mg, 1.2 mmol) in 2 mL of ethanol was added 0.5 mL ofconc. HCl and the mixture was refluxed overnight. The reaction wasevaporated and purified by preparative HPLC (20-50% acetonitrile+0.15%trifluoroacetic acid in water, over 15 min.), followed by columnchromatography (PE:EtOAc=3:1˜EtOAc:MeOH=10:1) to give Compound 133 (67mg, yield 34.3%). ¹H NMR (CD₃OD 400 MHz): δ 9.18 (s, 1H), 8.42 (d, J=5.6Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.76 (d, J=6.0 Hz, 1H),7.65 (d, J=2.0 Hz, 1H), 7.48 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.17 (d, J=1.6Hz, 1H), 7.07-7.06 (m, 3H), 6.95-6.93 (m, 2H), 5.45 (s, 1H), 4.13-4.02(m, 2H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 483.3 [M+1]⁺.

Example 134 Compound 134,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-(3-methoxyphenyl)-1-(pyridin-3-yl)ethanone(Intermediate 69) (60 mg, 0.26 mmol),3-ethoxy-4-hydroxy-5-nitro-benzaldehyde (55.8 mg, 0.26 mmol) and urea(46.8 mg, 0.78 mmol) in 3 mL of ethanol was added 0.2 mL of concentratedHCl. The mixture was refluxed for 2 days. After the solvent was removed,the residue was purified by reverse-phase preparatory HPLC (26-53%acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroaceticacid, over 15 min.) to give Compound 134 (30 mg, yield 24.6%). ¹H NMR(CD₃OD 400 MHz): δ 8.75 (s, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.01 (dd,J₁=6.0 Hz, J₂=8.4 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.08 (m, 2H), 6.75(dd, J₁=2.4 Hz, J₂=8.4 Hz, 1H), 6.55 (s, 1H), 6.49 (d, J=3.6 Hz, 1H),5.53 (s, 1H), 4.02 (m, 2H), 3.64 (s, 3H); 1.39 (t, J=6.8 Hz, 3H); MS(ESI): m/z 463.1 [M+1]⁺.

Example 135 Compound 135,3-ethoxy-2-hydroxy-5-(5-(3-methoxyphenyl)-2-oxo-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a solution of 2-(3-methoxyphenyl)-1-(pyridin-3-yl)ethanone(Intermediate 69) (70 mg, 0.31 mmol),3-ethoxy-5-formyl-2-hydroxy-benzoic acid (Intermediate 62) (65 mg, 0.31mmol) and urea (60 mg, 1.0 mmol) in 3 mL of ethanol was added 0.2 mL ofconcentrated HCl, then the mixture was refluxed for 2 days. The solventwas removed and the residue was purified by reverse-phase preparatoryHPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1%trifluoroacetic acid, over 15 min.) to give Compound 135 (25 mg, yield16.9%). ¹H NMR (CD₃OD 400 MHz): δ 8.73 (d, J=6.8 Hz, 1H), 8.72 (s, 1H),8.52 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H),7.01 (d, J=2.4 Hz, 1H), 7.17 (m, 3H), 6.98 (d, J=2.4 Hz, 1H), 6.74 (dd,J₁=2.4 Hz, J₂=8.4 Hz, 1H), 6.50 (dd, J₁=2.4 Hz, J₂=12.0 Hz, 2H), 5.41(s, 1H); 4.00 (m, 2H). 3.63 (s, 3H), 1.36 (t, J=6.8 Hz, 3H); MS (ESI):m/z 462.1 [M+1]⁺.

Example 136 Compound 136,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(pyridin-4-yl)-2-(thiophen-3-yl)ethanone (Intermediate70) (180 mg, 0.89 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (188 mg,0.89 mmol), urea (160 mg, 2.70 mmol), conc. hydrochloric acid (0.5 mL)in ethanol (3 mL) was refluxed for 45 hours. The mixture wasconcentrated and purified by prep-HPLC (0.1% TFA as additive). To theresidue was added HCl/MeOH (2 mL, 2 N) and concentrated to give Compound136 as HCl salt (24.3 mg, yield 6%). HNMR (DMSO-d₆ 400 MHZ): δ 10.31(brs, 1H), 9.03 (s, 1H), 8.72 (d, J=6.4 Hz, 2H), 7.71 (s, 1H), 7.61 (d,J=6.0 Hz, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=4.8, 2.8 Hz, 1H),7.17 (d, J=1.6 Hz, 1H), 7.02 (dd, J=2.8, 1.2 Hz, 1H), 6.50 (dd, J=5.2,1.2 Hz, 1H), 5.32 (d, J=2.4 Hz, 1H), 4.05 (q, J=6.8 Hz, 2H), 1.34 (t,J=6.8 Hz, 3H). MS (ESI): m/z 438.9 [M+H]⁺.

Example 137 Compound 137,4-(4-hydroxy-3-(2-hydroxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To the solution of 4-hydroxy-3-(2-hydroxyethoxy)-5-nitrobenzaldehyde(Intermediate 71) (60 mg, 0.27 mmol), 1,2-diphenyl-ethanone (53 mg, 0.27mmol) and urea (48.6 mg, 0.81 mmol) in 4 mL of ethanol was added 0.2 mLof concentrated HCl, and the mixture was stirred at reflux for 2 days.The mixture was concentrated and purified by reverse-phase preparatoryHPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1%trifluoroacetic acid, over 15 min.) to give Compound 137 (28 mg, yield23.7%). ¹H NMR (DMSO-d₆ 400 MHz): δ 10.23 (s, 1H), 8.75 (s, 1H), 7.55(s, 1H), 7.46 (s, 1H), 7.26 (m, 6H), 7.02 (m, 3H), 6.83 (d, J=7.2 Hz,2H), 5.19 (d, J=2.4 Hz, 1H), 3.99 (m, 2H), 3.75 (m, 2H); MS (ESI): m/z448.1 [M+1]⁺.

Example 138 Compound 138,2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of methyl 4-formyl-2-hydroxybenzoate (Intermediate 84) (125mg, 0.69 mmol), 1,2-diphenylethanone (136.2 mg, 0.69 mmol), urea (124.8mg, 2.08 mmol), concentrated hydrochloric acid (1.0 mL) in ethanol (5mL) was heated at 90° C. for 40 hours. Followed standard aqueous/EtOAcworkup procedure to give crude ethyl2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate(200 mg, yield 69.5%). To a solution of this crude material (200 mg,0.483 mmol) in water (5 mL) and ethanol (5 mL) was added sodiumhydroxide (38.64 mg, 0.966 mmol) at 0° C. The mixture was stirred at 30°C. for 4 hours, then partitioned between ethyl acetate (70 mL) and water(50 mL). The organic layer was discarded and the aqueous layer wasadjusted to pH=3 by hydrochloric acid (2M). Followed a standardaqueous/EtOAc workup. The residue was purified by preparative HPLC togive Compound 138 (31.3 mg, yield 16.8%). HNMR (DMSO-d₆ 400 MHz): δ11.27 (s, 1H), 8.71 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.26 (s, 1H),7.25-7.19 (m, 5H), 7.03-6.99 (m, 3H), 6.93 (d, J=8.0 Hz, 1H), 6.87 (s,1H), 6.81 (d, J=6.4 Hz, 2H), 5.16 (d, J=2.8 Hz, 1H); MS (ESI): m/z 387.0[M+H]⁺.

Example 139 Compound 139,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-5-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 1-(1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)ethanone(Intermediate 72) (90 mg, 0.32 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (110 mg, 0.52 mmol) and urea (52mg, 0.87 mmol) in EtOH (4 mL) was added concentrated HCl (0.1 mL). Thereaction was refluxed overnight. Purified by column chromatography andpreparative HPLC to give Compound 139 as a yellow solid (32 mg, yield:16.7%). ¹HNMR (DMSO-d₆ 400 MHz): δ 10.44 (s, 1H), 8.91 (s, 1H), 7.75 (s,1H), 7.57 (d, J=1.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.34-7.36 (m, 2H),7.06-7.07 (m, 1H), 6.39 (d, J=2.0 Hz, 1H), 6.21 (d, J=4.8 Hz, 1H), 5.42(d, J=2.4 Hz, 3H), 4.14 (q, J=7.2 Hz, 2H), 3.62 (s, 3H), 1.42 (t, J=7.2Hz, 3H); MS (ESI): m/z 442.0 [M+1]⁺.

Example 140 Compound 140,2-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 4-formyl-2-nitrobenzoic acid (Intermediate 73) (120 mg,0.615 mmol), 1,2-diphenylethanone (120 mg, 0.615 mmol), urea (110 mg,1.845 mmol), hydrochloric acid (0.5 mL) in ethanol (2 mL) was heated at92° C. for 41 hours. A standard aqueous/EtOAc workup was followed togive crude ethyl2-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate(170 mg, yield 62.3%). This was taken up in water (3 mL) and ethanol (3mL) and sodium hydroxide (30.6 mg, 0.766 mmol) was added at 0° C., andthe mixture was stirred at 28° C. for 5 hours. The reaction mixture waspartitioned between water (30 mL) and ethyl acetate (70 mL). The organiclayer was discarded and the aqueous layer was adjusted to pH=3 withhydrochloric acid (2 mol/L). Then the resulting mixture was extractedwith ethyl acetate (30 mL×3). The organic layers were washed with brine(50 mL), dried over sodium sulfate and evaporated. Purified bypreparative HPLC to give Compound 140 (37.1 mg, yield 23.3%). HNMR(DMSO-d₆ 300 MHz): δ 11.38 (s, 1H), 8.82 (s, 1H), 7.84 (d, J=7.8 Hz,2H), 7.75-7.69 (m, 2H), 7.24 (m, 5H), 7.04-7.01 (m, 3H), 6.83 (d, J=7.8Hz, 2H), 5.45 (d, J=2.7 Hz, 1H); MS (ESI): m/z 416.0 [M+H]⁺.

Example 141 Compound 141,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-ethylphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-(3-ethylphenyl)-1-phenylethanone (Intermediate 74) (90mg, 0.40 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (84.5 mg, 0.40mmol), urea (72 mg, 1.2 mmol), conc. HCl (0.2 mL) in ethanol (1 mL) wasstirred at 115° C. for 6 h. Solvent was removed in vacuo andpurification by prep-HPLC (0.1% TFA as additive) gave Compound 141 (46.3mg, yield 25%). ¹H NMR (DMSO 400 MHz): δ 10.29 (brs, 1H), 8.71 (s, 1H),7.54 (s, 1H), 7.46 (s, 1H), 7.28-7.20 (m, 5H), 6.97-6.91 (m, 1H), 7.43(d, J=7.6 Hz, 1H), 6.71-6.61 (m, 2H), 5.22 (d, J=2.8 Hz, 1H), 4.04 (q,J=6.8 Hz, 2H), 2.29 (q, J=7.6 Hz, 2H) 1.33 (t, J=6.8 Hz, 3H), 0.85 (t,J=7.6 Hz, 3H), MS (ESI): m/z 460.3 [M+H]⁺.

Example 142 Compound 142,3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone(Intermediate 57) (250 mg, 1.2 mmol), 3-ethoxy-5-formyl-2-hydroxybenzoicacid (Intermediate 62) (237 mg, 1.2 mmol), urea (217.8 mg, 3.6 mmol) andconc. HCl (0.2 mL) in EtOH (10 mL) was refluxed overnight. The mixturewas concentrated under reduced pressure to dryness and purified byprep-HPLC (0.1% TFA as additive) to give Compound 142 (120 mg, yield23%). ¹H NMR (DMSO-d₆ 400 MHz): δ 8.39 (s, 1H), 7.60 (s, 1H), 7.40-7.34(m, 3H), 7.00-6.96 (m, 3H), 6.59 (dd, J=0.8 Hz, 4.8 Hz, 1H), 4.96 (d,J=2.8 Hz, 1H), 3.99-3.90 (m, 2H), 3.74 (s, 3H), 1.31 (t, J=6.8 Hz, 3H);MS (ESI): m/z 441.0 [M+1]⁺;

Example 143 Compound 143,(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

The two enantiomers of Compound 116 (see Example 116) were separated bychiral SFC separation (OD 250 mm*20 mm, 10 um) eluting withsupercritical CO₂:MeOH=60:40 to give the front fraction as Compound 143(188.5 mg, yield 21%). ¹H NMR (DMSO 400 MHz): δ 10.30 (s, 1H), 8.91 (s,1H), 8.52-8.50 (m, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H),7.62 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.25-7.15 (m,2H), 6.91 (d, J=1.6 Hz, 1H), 6.31 (m, 1H), 5.22 (d, J=2.4 Hz, 1H),4.10-4.00 (m, 2H), 1.33 (t, J=6.8 Hz, 3H); MS (ESI): m/z 438.9 [M⁺+H].

Example 144 Compound 144,(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

The two enantiomers of Compound 116 (see Example 116) were separated bychiral SFC separation (OD 250 mm*20 mm, 10 um) eluting withsupercritical CO₂:MeOH=60:40 to give the back fraction as Compound 144(197.6 mg, yield 22%). ¹H NMR (MeOD 400 MHz): δ 8.40-8.36 (m, 1H), 8.31(s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.34-7.29 (m,1H), 7.07-7.02 (m, 2H), 6.71 (d, J=2.0 Hz, 1H), 6.39 (dd, J=1.2 Hz, 1.2Hz, 1H), 5.21 (s, 1H), 4.02-3.93 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); MS(ESI): m/z 438.9 [M⁺+H].

Example 145 Compound 145,2-chloro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a mixture of methyl 2-chloro-4-formylbenzoate (Intermediate 75) (210mg, 1.1 mmol), 1,2-diphenylethanone (208 mg, 1.1 mmol), urea (191 mg,3.2 mmol) and conc. HCl (0.5 mL) in ethanol (2 mL) was refluxed at 95°C. for 30 hours. A standard aqueous/EtOAc workup procedure was followedto give crude ethyl2-chloro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate(360 mg). This was taken up in water (2.5 mL) and ethanol (2.5 mL) andsodium hydroxide (67 mg, 1.7 mmol) was added at 30° C. The resultingmixture was stirred at 40° C. for 6 hours. HCl (2 N) was added untilpH=3. A standard aqueous/EtOAc workup procedure was followed and crudewas purified by prep-HPLC (0.1% TFA as additive) to give Compound 145(57.3 mg, yield 17%). ¹H NMR (DMSO 400 MHz): δ 13.37 (brs, 1H), 8.76 (s,1H), 7.78 (d, J=7.6 Hz, 1H), 7.63 (s, 1H), 7.43-7.36 (m, 2H), 7.26-7.19(m, 5H), 7.05-6.98 (m, 3H), 6.81 (d, J=6.4 Hz, 2H), 5.28 (d, J=2.4 Hz,1H), MS (ESI): m/z 404.9 [M+H]⁺.

Example 146 Compound 146,(S)-3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

The two enantiomers of Compound 142 (see Example 142) were separated bychiral supercritical chromatography (SFC separation condition: Column:AS-SUM, 300*300 mm, 20 UM; Mobile Phase: 35% MeOH+DIEA, 40 ML/MIN;Detector Wavelength: 220 nm), the eluting solution for the first peakwas collected and evaporated under reduced pressure to give oneenantiomer as Compound 146 (30 mg, yield 25%). ¹H NMR (MeOHd4 300 MHz):δ 7.44 (d, J=2.0 Hz, 2H), 7.24-7.21 (m, 1H), 7.10 (s, 1H), 7.04 (s, 1H),6.85 (s, 1H), 6.59 (d, J=5.1 Hz, 1H), 5.07 (s, 1H), 3.99-3.96 (m, 2H),3.78 (s, 3H), 1.35 (t, J=6.9 Hz, 1H); MS (ESI): m/z 440.9 [M+1]⁺; [α]²⁰_(D)=0.118 (c=2.79 mg/mL, MeOH).

Example 147 Compound 147,(R)-3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

The two enantiomers of Compound 142 (see Example 142) were separated bychiral supercritical chromatography (see Example 146 for conditions) andthe eluting solution for the second peak was collected and evaporatedunder reduced pressure to give Compound 147 (27 mg, yield 23%). ¹H NMR(MeOD, 300 MHz TMS): δ 7.44 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 7.03(s, 1H), 6.84 (s, 1H), 6.58 (d, J=3.9 Hz, 1H), 5.06 (s, 1H), 4.00 (t,J=3.0 Hz, 1H), 3.78 (s, 3H), 1.35 (t, J=7.2 Hz, 1H). MS (ESI): m/z 441.0[M+1]⁺; [α]²⁰ _(D)=−0.094 (c=3.65 mg/mL, MeOH).

Example 148 Compound 148,(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

The two enantiomers of Compound 119 (see Example 119) were separated bychiral supercritical chromatography (SFC separation condition: Column:AS-SUM, 300*300 mm, 20 UM; Mobile Phase: 35% MeOH+DIEA, 40 ML/MIN;Detector Wavelength: 220 nm); the eluting solution for the first peakwas collected and evaporated under reduced pressure to give oneenantiomer as Compound 148 (630 mg, yield 48%). ¹H NMR (DMSO-d6 400MHz): δ 10.29 (s, 1H), 7.71 (s, 1H), 7.64-7.60 (m, 2H), 7.41-7.38 (m,2H), 7.11 (s, 2H), 6.64 (d, J=4.0 Hz, 1H), 5.52 (d, J=2.4 Hz, 1H), 5.14(d, J=2.4 Hz, 1H), 4.07-3.99 (m, 2H); 3.84 (s, 3H), 1.33 (t, J=6.8 Hz,3H); MS (ESI): m/z 442.1 [M+1]⁺; [α]²⁰ _(D)=0.160 (c=5.12 mg/mL, MeOH);

Example 149 Compound 149,(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

The two enantiomers of Compound 119 (see Example 119) were separated bychiral supercritical chromatography (see Example 148 for conditions);the eluting solution for the second peak was collected and evaporatedunder reduced pressure to give another enantiomer as Compound 149 (640mg, yield 49%). ¹H NMR (DMSO-d6, 400 MHz): δ 10.28 (s, 1H), 7.70 (s,1H), 7.62-7.59 (m, 2H), 7.41-7.37 (m, 2H), 7.11-7.09 (m, 2H), 6.64 (dd,J=1.2 Hz, 5.2 Hz, 1H), 5.52 (d, J=2.4 Hz, 1H), 5.13 (d, J=2.8 Hz, 1H),4.07-3.98 (m, 2H); 3.83 (s, 3H), 1.33 (t, J=6.8 Hz, 3H), MS (ESI): m/z442.0 [M+1]⁺; [α]²⁰ _(D)=−0.159 (c=52.75 mg/mL, MeOH).

Example 150 Compound 150,4-ethoxy-6-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one

To a solution of4-ethoxy-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbaldehyde (Intermediate76) (70 mg, 0.34 mmol), 1,2-diphenylethanone (70 mg, 0.36 mmol) and urea(82 mg, 1.4 mmol) in 5 mL of ethanol was added 0.2 ml con. HCl under N₂.The reaction mixture was refluxed overnight. The reaction mixture waspurified by prep-HPLC (0.1% TFA as additive) and solvent removed to giveCompound 150 as white solid (32 mg, yield 22%). ¹H NMR (CD₃OD 400 MHz):7.27 (m, 5H), 7.06-7.04 (m, 3H), 6.92-6.87 (m, 3H), 6.82 (s, 1H), 5.33(s, 1H), 4.14-4.08 (m, 2H), 1.41 (t, J=6.8 Hz, 3H). MS (ESI): m/z 428.2[M+1]⁺.

Example 151 Compound 151,3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

Step 1: Synthesis of4-(3-bromo-5-fluoro-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 3-bromo-5-fluoro-4-hydroxybenzaldehyde (Intermediate 77)(600 mg, 2.7 mmol), 1,2-diphenylethanone (538 mg, 2.7 mmol), urea (493mg, 8.2 mmol) and conc HCl (1 mL) in ethanol (4 mL) was heated at 95° C.for 50 hours. The mixture was evaporated under reduced pressure and waspurified by silica gel column chromatography (petroleum ether/ethylacetate=2:1) to give product (400 mg, yield 33%) as yellow solid. ¹H NMR(DMSO 300 MHz): δ10.41 (brs, 1H), 8.66 (s, 1H), 7.45 (s, 1H), 7.24-6.95(m, 10H), 6.75 (d, J=7.8 Hz, 2H), 5.07 (s, 1H).

Step 2: Synthesis of methyl3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate

To a mixture of the above from Step 1 (200 mg, 0.50 mmol) in methanol(10 mL) was added Pd(dppf)Cl₂ (80 mg) at 27° C. under carbon monoxideatmosphere (40 psi) for 25 hours. After being cooled, the mixture wasfiltered and the filtrate was evaporated under reduced pressure to giveproduct (200 mg, yield 100%).

Step 3: Synthesis of3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a mixture of the above from Step 2 (200 mg, 0.50 mmol) in water (3.0mL) and ethanol (3.0 mL) was added lithium hydroxide (34.5 mg, 1.4 mmol)at 30° C. The resulting mixture was stirred at 40° C. for 14 hours. Thereaction mixture was acidified with 2N of HCl to pH=3. Followed astandard aqueous/EtOAc workup procedure and then purified by prep-HPLC(0.1% TFA as additive) to give Compound 151 (37.1 mg, yield 19%). ¹H NMR(DMSO 300 MHz): δ8.69 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.36 (d,J=11.7 Hz, 1H), 7.22-7.16 (m, 5H), 7.01-6.95 (m, 3H), 6.78-6.72 (m, 2H),5.12 (s 1H), MS (ESI): m/z 405.0 [M+H]⁺.

Example 152 Compound 152,2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

Step 1: Synthesis of4-(4-bromo-3-fluorophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 4-bromo-3-fluorobenzaldehyde (100 mg, 0.5 mmol),1,2-diphenylethanone (118 mg, 0.6 mmol) and urea (90 mg, 1.5 mmol) inethanol (3 mL) was added conc. HCL (0.1 mL). The mixture was refluxedunder N₂ atmosphere for 6 hrs. Solvent was removed; purified by silicagel column chromatography (PE:EtOAc=10:1 to PE:EtOAc=1:1) to giveproduct (130 mg, yield 62%). ¹H NMR (DMSO-d₆ 400 MHz): δ 8.74 (s, 1H),7.74-7.68 (m, 1H), 7.54 (s, 1H), 7.26-7.15 (m, 7H), 7.03-6.95 (m, 3H),6.81-6.79 (m, 2H), 5.24 (d, J=2.8 Hz, 1H).

Step 2: Synthesis of methyl2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate

To a solution of the above compound from Step 1 (100 mg, 0.24 mmol) andtriethylamine (0.2 mL) in methanol (20 mL) was added dppf (65 mg, 0.12mmol) and Pd(OAc)₂ (53 mg, 0.24 mmol). The reaction was stirred under COatmosphere (35 psi) at 75° C. overnight. The reaction mixture wasfiltered, the filtrate was concentrated, and then purified by silica gelcolumn chromatography (PE:EtOAc=10:1 to PE:EtOAc=1:1) to give product(90 mg, 95%).

Step 3: Synthesis of2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

Followed procedure described in Step 3 of Example 151, where reactionwas run at 10-15° C. for 1 hr. Purified by silica gel columnchromatography (PE:EtOAc=20:1 to PE:EtOAc=5:1) and prep-HPLC (0.1% TFAas additive) to give compound 152 (20 mg, yield 23%). ¹H NMR (DMSO-d₆400 MHz): δ 13.13 (s, 1H), 8.66 (s, 1H), 7.79-7.75 (m, 1H), 7.54 (s,1H), 7.20-7.05 (m, 7H), 6.96-6.90 (m, 3H), 6.73-6.71 (m, 2H), 5.20 (d,J=2.8 Hz, 1H). MS (ESI): m/z 431.9[M+1]⁺.

Example 153 Compound 153,2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a mixture of methyl 2-ethoxy-4-formyl-6-nitrobenzoate (Intermediate78) (100 mg, 0.4 mmol), 1,2-diphenylethanone (116 mg, 0.6 mmol) and urea(72 mg, 1.2 mmol) in ethanol (3 mL) was added conc. HCl (0.1 mL).Refluxed under N₂ atmosphere overnight. Concentrated under reducedpressure, then purified by silica gel column chromatography(PE:EtOAc=10:1 to PE:EtOAc=1:1) to give methyl2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate(110 mg, yield 58%). This was taken up in ethanol (5 mL) and aq. NaOH(0.5 M, 2 mL, 1 mmol) was added. The mixture was stirred under N₂atmosphere at 60° C. for 5 hrs. The reaction mixture was acidified withconc. HCl (3 mL), and then extracted with a solution(DCM:i-propanol=10:1, 30 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by prep-HPLC (0.1% TFA as additive) to giveCompound 153 (58 mg, yield 55%). ¹H NMR (DMSO-d₆ 400 MHz): δ 13.60 (s,1H), 8.83 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.28-7.21(m, 5H), 7.07-7.00 (m, 3H), 6.85 (d, J=6.8 Hz, 2H), 5.42 (d, J=2.4 Hz,1H), 4.12-4.00 (m, 2H), 1.26 (t, J=7.0 Hz, 3H). MS (ESI): m/z460.1[M+1]⁺.

Example 154 Compound 154,4-(4-hydroxy-3-nitro-5-(trifluoromethyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a mixture of 4-hydroxy-3-nitro-5-(trifluoromethyl)benzaldehyde(Intermediate 79) (100 mg, 0.40 mmol), 1,2-diphenylethanone (83 mg, 0.40mmol), urea (77 mg, 1.30 mmol) and conc. HCl (0.05 mL) in ethanol (1 mL)was heated at 90° C. for 37 hours. Solvent was removed under reducedpressure and the residue was purified by prep-HPLC (0.1% TFA asadditive) to give Compound 154 (31.2 mg, yield 30%) as yellow solid. ¹HNMR (DMSO 300 MHz): δ 8.81 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.62 (s,1H), 7.25-7.17 (m, 5H), 7.03-6.96 (m, 3H), 6.78 (d, J=7.2 Hz, 2H), 5.34(s, 1H), MS (ESI): m/z 456.0 [M+H]⁺.

Example 155 Compound 155,4-(4-hydroxy-3-(2-methoxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of 4-hydroxy-3-(2-methoxyethoxy)-5-nitrobenzaldehyde(Intermediate 80) (200 mg, 0.83 mmol), 1,2-diphenylethanone (196 mg, 1.0mmol) and urea (150 mg, 2.5 mmol) in ethanol (3 mL) was added conc. HCl(0.2 mL), then the resulting mixture was refluxed for 2 days. Themixture was concentrated under reduced pressure and purified byprep-HPLC (0.1% TFA as additive) to give Compound 155 (162 mg, yield42%) as yellow solid. ¹H NMR (MeOD 400 MHz) δ 7.62 (d, J=1.6 Hz, 1H),7.27-7.24 (m, 6H), 7.07-7.03 (m, 3H), 6.91-6.86 (m, 2H), 5.37 (s, 1H),4.17-4.10 (m, 2H), 3.76 (t, J=4.4 Hz, 2H), 3.43 (s, 3H). MS (ESI): m/z462.1 [M+1]⁺.

Example 156 Compound 156,4-(4-hydroxy-3-nitro-5-propylphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of4-(tert-butyldimethylsilyloxy)-3-nitro-5-propylbenzaldehyde(Intermediate 81) (100 mg, 0.31 mmol), 1,2-diphenylethanone (78 mg, 0.40mmol) and urea (60 mg, 1.0 mmol) in ethanol (5 mL) was added conc. HCl(0.2 mL) and the reaction mixture was refluxed under N₂ atmosphereovernight. Reaction was cooled and then purified by prep-HPLC (0.1% TFAas additive). The solution was concentrated under reduced pressure togive Compound 156 as a yellow solid (21 mg, yield 16%). ¹H NMR (CD₃OD400 MHz): δ 7.95 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 5H),7.06-7.03 (m, 3H), 6.89-6.86 (m, 2H), 5.39 (s, 1H), 2.70 (t, J=7.6 Hz,2H), 1.66-1.59 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). MS (ESI): m/z 430.2[M+1]⁺.

Example 157 Compound 157,4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoicacid

To a solution of methyl 4-formyl-2-(trifluoromethyl)benzoate(Intermediate 82) (180 mg, 0.80 mmol), 1,2-diphenyl-ethanone (222 mg,0.80 mmol) and urea (145 mg, 2.4 mmol) in ethanol (3 mL) was added conc.HCl (0.2 mL), then the resulting mixture was refluxed for 2 days. Themixture was concentrated in vacuo to give methyl4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoate,which was used crude. This was taken up in MeOH (3 mL) and 2 N aq. NaOH(3 mL) was added; then the resulting mixture was stirred at 40° C. for 3hours. The mixture was acidified with aqueous HCl till pH=5 and thenfollowed a standard aqueous/EtOAc workup. Purified by prep-HPLC (0.1%TFA as additive) to give Compound 157 (34 mg, two steps yield 10%) aswhite solid. ¹H NMR (MeOD 400 MHz) δ 7.82 (d, J=8.0 Hz, 1H), 7.72-7.67(m, 2H), 7.36-7.20 (m, 5H), 7.10-7.05 (m, 3H), 6.88-6.85 (m, 2H), 5.30(s, 1H). MS (ESI): m/z 439.2 [M+1]⁺.

Example 158 Compound 158,2-fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a solution of methyl 2-fluoro-4-formyl-6-hydroxybenzoate(Intermediate 83) (150 mg, 0.76 mmol), 1,2-diphenylethanone (150 mg,0.76 mmol) and urea (144 mg, 2.4 mmol) in ethanol (5 mL) was added conc.HCl (0.2 mL) and the reaction mixture was refluxed under N₂ overnight.Removed solvent in vacuo and the residue (320 mg) was used withoutfurther purification. A mixture of this intermediate compound (320 mg)and aqueous NaOH (2 M, 10 mL) in MeOH (10 mL) was stirred at 40° C. for3 hours. The resulting mixture was cooled and acidified with aqueous HCl(2 M, 12 mL) and a standard aqueous/EtOAc workup was followed.Purification by prep-HPLC (0.1% TFA as additive) gave Compound 158 as ayellow solid (41 mg, two step yield 13%). ¹H NMR (CD₃OD 400 MHz): δ7.30-7.20 (m, 5H), 7.10-7.05 (m, 3H), 6.91-6.88 (m, 2H), 6.75 (s, 1H),6.65 (d, J=11.6 Hz, 1H), 5.29 (s, 1H). MS (ESI): m/z 405.0 [M+1]⁺.

Example 159 Compound 159,2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl) ethanone(Intermediate 57) (200 mg, 0.97 mmol), methyl 4-formyl-2-hydroxybenzoate(Intermediate 84) (175 mg, 0.97 mmol), urea (180 mg, 3.0 mmol) and conc.HCl (0.2 mL) in EtOH (5 mL) was refluxed under N₂ overnight. Solvent wasremoved in vacuo and the residue was taken up in a mixture of MeOH (10mL) and aq. NaOH (2 M, 10 mL) and was stirred at 40° C. under N₂atmosphere for 5 hours. The resulting mixture was cooled to roomtemperature, and then acidified with aq. HCl (2 M, 12 mL) to pH=5.Followed a standard aqueous/EtOAc workup and purified by prep-HPLC (0.1%TFA as additive) to give Compound 159 (140 mg, two steps yield 36%). ¹HNMR (DMSO-d6 400 MHz): δ 11.09 (brs, 1H), 8.29 (s, 1H), 7.59 (d, J=8.4Hz, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 7.22-7.20 (m, 1H), 6.88-6.83 (m,2H), 6.72-6.69 (m, 1H), 6.66 (s, 1H); 6.43 (d, J=4.8 Hz, 1H), 4.87 (s,1H), 3.59 (s, 3H); MS (ESI): m/z 397.3 [M+H]⁺.

Example 160 Compound 160,2-hydroxy-4-(2-oxo-5-phenyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 2-phenyl-1-(pyridin-3-yl)ethanone (Intermediate 31) (220mg, 1.1 mmol), methyl 4-formyl-2-hydroxybenzoate (Intermediate 84) (200mg, 1.1 mmol), urea (198 mg, 3.3 mmol) and conc. HCl (0.2 mL) in EtOH (5mL) was refluxed overnight. Solvent was removed in vacuo and the residuewas taken up in a mixture of MeOH (10 mL) and aq. NaOH (2 M, 10 mL) andwas stirred at 40° C. for 5 hours. The resulting mixture was cooled toroom temperature, and then acidified with aq. HCl (2 M, 12 mL) to pH=5.Followed a standard aqueous/EtOAc workup and purified by prep-HPLC (0.1%TFA as additive) to give Compound 160 (50 mg, two steps yield 12%). ¹HNMR (DMSO-d6 400 MHz): δ 8.94 (s, 1H), 8.48 (d, J=3.6 Hz, 1H), 8.40 (s,1H), 7.76 (m, 2H), 7.65 (s, 1H), 7.42-7.38 (m, 1H), 7.06-7.00 (m, 3H),6.93 (d, J=8.0 Hz, 1H), 6.90-6.84 (m, 3H), 5.25 (s, 1H). MS (ESI): m/z388.2 [M+1]⁺.

Example 161 Compound 161,2-ethoxy-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of methyl 2-ethoxy-4-formyl-6-hydroxybenzoate (Intermediate85) (150 mg, 0.67 mmol), 1,2-diphenylethanone (137 mg, 0.70 mmol), urea(120 mg, 2.0 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxedunder N₂ overnight. The mixture was concentrated under reduced pressure.The residue was taken up in MeOH (10 mL) and aq. NaOH (2 M, 10 mL) andwas stirred at 40° C. under N₂ for 5 hours. The resulting mixture wascooled to room temperature, and then acidified with aqueous HCl (2 M, 12mL), followed by a standard aqueous/EtOAc workup and purification byprep-HPLC (0.1% TFA as additive) to give Compound 161 (38 mg, 2-stepyield 13%). ¹H NMR (CD₃OD 400 MHz): δ 7.25-7.20 (m, 5H), 7.08-7.00 (m,3H), 6.89-6.84 (m, 2H), 6.62 (d, J=1.6 Hz, 1H), 6.47 (d, J=1.6 Hz, 1H),5.24 (s, 1H), 4.17-4.04 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). MS (ESI): m/z431.5 [M+1]⁺.

Example 162 Compound 162,4-(4-(2H-tetrazol-5-yl)phenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 4-(2H-tetrazol-5-yl)benzaldehyde (106 mg),2-phenyl-1-(pyridin-3-yl)ethanone (Intermediate 31) (100 mg, 0.51 mmol),urea (120 mg, 2.0 mmol) and conc. HCl (0.2 mL) in EtOH (5 mL) wasrefluxed under N₂ overnight. The mixture was concentrated under reducedpressure and purified by prep-HPLC (0.1% TFA as additive) to giveCompound 162 (50 mg, 2-step yield 25%). ¹H NMR (DMSO-d₆ 400 MHz): δ 8.97(s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.89 (s, 1H), 8.05-7.97 (m, 2H), 7.85(d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.49-7.44 (m,1H), 7.07-7.00 (m, 3H), 6.89-6.85 (m, 2H), 5.38 (s, 1H). MS (ESI): m/z396.4 [M+1]⁺

Example 163 Compound 163,2-chloro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

To a solution of methyl 2-chloro-4-formyl-6-hydroxybenzoate(Intermediate 86) (150 mg, 0.70 mmol), 1,2-diphenylethanone (165 mg,0.84 mmol) and urea (126 mg, 2.1 mmol) in ethanol (5 mL) was added conc.HCl (0.2 mL) and mixture was refluxed under N₂ overnight. The mixturewas concentrated under reduced pressure. The residue was taken up inaqueous NaOH (2 M, 5 mL) and MeOH (5 mL) and was stirred at 50° C. underN₂ atmosphere for 6 hours. The resulting mixture was cooled to roomtemperature and acidified with aqueous HCl (2 M, 6 mL), followed by astandard aqueous/EtOAc workup and purification by prep-HPLC (0.1% TFA asadditive) to give Compound 163 (75 mg, 2-step yield 26%). ¹H NMR (CD₃OD400 MHz): δ 7.30-7.25 (m, 5H), 7.15-7.05 (m, 3H), 6.95-6.87 (m, 4H),5.26 (s, 1H). MS (ESI): m/z 421.4 [M+1]⁺.

Example 164 Compound 164,4-(4-(2H-tetrazol-5-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1,2-diphenylethanone (150 mg, 0.76 mmol),4-(2H-tetrazol-5-yl)benzaldehyde (400 mg), urea (230 mg, 3.8 mmol) andconc. HCl (0.5 mL) in EtOH (5 mL) was refluxed under N₂ overnight.Solvent was removed in vacuo and purified by prep-HPLC (0.1% TFA asadditive) to give Compound 164 (45 mg, yield 15%) as off-white solid. ¹HNMR DMSO-d₆ 400 MHz): δ 8.75-8.68 (m, 1H), 8.00 (d, J=8.0 Hz, 2H),7.65-7.60 (m, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.28-7.16 (m, 5H), 7.06-6.96(m, 3H), 6.84-6.78 (m, 2H), 5.28 (s, 1H). MS (ESI): m/z 395.5 [M+1]⁺.

Example 165 Compound 165,2-hydroxy-6-methoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of methyl 4-formyl-2-hydroxy-6-methoxybenzoate (Intermediate87) (150 mg, 0.76 mmol), 1,2-diphenylethanone (160 mg, 0.76 mmol), urea(150 mg, 2.5 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxedunder N₂ overnight. The mixture was concentrated in vacuo. The residuewas taken up in MeOH (10 mL) and aq. NaOH (2 M, 10 mL) and was stirredat 50° C. under N₂ for 5 hours. The resulting mixture was cooled, andthen acidified with aqueous HCl (2 M, 12 mL) to pH=3 followed by astandard aqueous/EtOAc workup and purification by prep-HPLC (0.1% TFA asadditive) to give Compound 165 (31 mg, 2-step yield 10%). ¹H NMR (CD₃OD400 MHz): δ 7.30-7.20 (m, 5H), 7.12-7.06 (m, 3H), 6.94-6.88 (m, 2H),6.67 (d, J=1.6 Hz, 1H), 6.50 (d, J=1.6 Hz, 1H), 5.29 (s, 1H), 3.85 (s,3H). MS (ESI): m/z 417.4 [M+1]⁺.

Example 166 Compound 166,4-(4-(2H-tetrazol-5-yl)phenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate56) (80 mg, 0.39 mmol), 4-(2H-tetrazol-5-yl)benzaldehyde (300 mg), urea(120 mg, 2.0 mmol) and conc. HCl (0.5 mL) in EtOH (5 mL) was refluxedunder N₂ overnight. The mixture was concentrated under reduced pressureand purified by prep-HPLC (0.1% TFA as additive) to give Compound 166(56 mg, yield 35%) as yellow solid. ¹H NMR (CD₃OD 400 MHz): δ 8.71-8.61(m, 2H), 8.30 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.85-7.78 (m,1H), 7.65 (d, J=8.0 Hz, 2H), 7.22 (dd, J=2.8 Hz, J=4.8 Hz, 1H), 6.89(dd, J=1.6 Hz, J=3.2 Hz, 1H), 6.56 (dd, J=1.2 Hz, J=5.2 Hz, 1H), 5.50(s, 1H). MS (ESI): m/z 402.3 [M+1]⁺.

Example 167 Compound 167,2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

A mixture of 1-(1-methyl-1H-pyrazol-4-yl)-2-phenylethanone (Intermediate88) (150 mg, 0.75 mmol), methyl 4-formyl-2-hydroxybenzoate (Intermediate84) (135 mg, 0.75 mmol), urea (138 mg, 2.3 mmol) and conc. HCl (0.5 mL)in EtOH (5 mL) was refluxed under N₂ atmosphere overnight. The mixturewas concentrated under reduced pressure. The residue was taken up inMeOH (10 mL) and aq. NaOH (2 M, 10 mL) and was stirred at 60° C. underN₂ overnight. The mixture was cooled, and then acidified with aqueousHCl (2 M, 12 mL) to pH=3 followed by a standard aqueous/EtOAc workup andpurification by prep-HPLC (0.1% TFA as additive) to give Compound 167(58 mg, 2-step yield 20%) as off-white solid. ¹H NMR (CD₃OD 400 MHz): δ7.81 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.25-7.20 (m, 3H), 6.88-6.78 (m,3H), 6.84 (d, J=8.0 Hz, 1H), 6.82 (s, 1H), 5.17 (s, 1H), 3.77 (s, 3H).MS (ESI): m/z 390.7 [M+1]⁺.

Example 168 Compound 168,(R)-2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

The two enantiomers of Compound 159 (see Example 159) were separated bychiral supercritical chromatography (SFC separation condition: Column:AS-SUM, 300*300 mm, 20 UM; Mobile Phase: 35% MeOH+DIEA, 40 ML/MIN;Detector Wavelength: 220 nm), the eluting solution for the first peakwas collected and evaporated in vacuo to give one enantiomer as Compound168 (40 mg, yield 40%) as yellow solid. ¹H NMR (DMSO-d6, 400 MHz): δ8.49 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.56 (s, 1H),7.43-7.40 (m, 1H), 7.11 (s, 1H), 7.05 (d, J=1.6 Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.84 (s, 1H), 6.64 (d, J=4.8 Hz, 1H); 5.09-5.00 (m, 1H), 3.83(s, 3H). MS (ESI): m/z 396.9 [M+1]⁺;

Example 169 Compound 169,(S)-2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid

The two enantiomers of Compound 159 (see Example 159) were separated bychiral supercritical chromatography (see example 168 for columnconditions). The eluting solution for the second peak was collected andevaporated under reduced pressure to give another enantiomer as Compound169 (43 mg, yield 43%) as yellow solid. ¹H NMR (DMSO-d6, 400 MHz): δ8.50 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.57 (s, 1H),7.44-7.41 (m, 1H), 7.09 (s, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.84 (s, 1H), 6.64 (d, J=5.2 Hz, 1H); 5.08-5.00 (m, 1H), 3.81(s, 3H). MS (ESI): m/z 396.9 [M+1]⁺.

Example 170 Compound 170,4-(3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one

To a solution of3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrobenzaldehyde (Intermediate89) (100 mg, 0.39 mmol), 1,2-diphenyl-ethanone (77 mg, 0.39 mmol) andurea (70 mg, 1.2 mmol) in ethanol (3 mL) was added conc. HCl (0.2 mL);the resulting mixture was refluxed overnight. The mixture wasconcentrated and purified by prep-HPLC (0.1% TFA as additive) to giveCompound 170 (45 mg, yield 22%) as yellow solid. ¹H NMR (MeOD 400 MHz) δ7.81 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.38-7.25 (m, 5H),7.16-7.04 (m, 3H), 6.98-6.88 (m, 2H), 5.47 (s, 1H), 4.46-4.35 (m, 2H),3.71-3.62 (m, 2H), 3.08 (s, 6H). MS (ESI): m/z 475.1 [M+1]⁺.

Example 171 Compound 171,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 2-phenyl-1-(tetrahydrofuran-2-yl)ethanone (Intermediate 90)(522 mg, 2.75 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (695 mg, 3.3mmol), and urea (495 mg, 8.25 mmol) in anhydrous EtOH (4 mL) was addedconcentrated HCl solution (0.2 mL), the reaction mixture was refluxedfor 14 hours. The reaction mixture was concentrated, and purified bycolumn chromatography and preparative HPLC to give product, contaminatedwith an impurity (21 mg). This was further purified by preparative TLCand preparative HPLC to give Compound 171 (14 mg). ¹H NMR (DMSO-d₆ 400MHz): δ 10.170 (s, 1H), 8.318 (s, 1H), 7.629 (d, J=2.4 Hz, 1H),7.276-7.344 (m, 5H), 7.066-7.163 (m, 2H), 5.384 (s, 1H), 4.245 (d, J=4.0Hz, 1H), 3.844-4.025 (m, 4H), 1.964-2.220 (m, 4H), 1.227-1.262 (t, J=3.0Hz, 3H); MS (ESI): m/z 426.1 [M+1]⁺.

Example 172 Compound 172,6-cyclopentyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-cyclopentyl-2-phenylethanone (Intermediate 91) (1.6 mmol,300 mg), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (1.91 mmol, 404 mg), andurea (4.8 mmol, 288 mg) in anhydrous ethanol (5 mL) was addedconcentrated HCl (0.2 mL), the above mixture was refluxed for 13 hours.The reaction mixture was concentrated and the residue was purified bycolumn chromatography, followed by preparative HPLC to afford theproduct Compound 172 as yellow solid (20 mg, yield: 2.96%). ¹H NMR (DMSO400 MHz): δ 10.23 (s, 1H), 8.25 (s, 1H), 6.98-7.33 (m, 8H), 5.00 (d,J=2.4 Hz, 1H), 3.94-4.04 (m, 2H), 2.65-2.69 (t, J=9.2 Hz, 1H), 1.24-1.79(m, 11H); MS (ESI): m/z 424.1 [M+1]⁺.

Example 173 Compound 173,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-3-yl)-3,4-dihydropyrimidin-2(1H)-one

To a solution of 2-phenyl-1-(tetrahydrofuran-3-yl)ethanone (Intermediate92) (60 mg, 0.32 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (67.5 mg,0.32 mmol) and urea (57.4 mg, 0.96 mmol) in 20 mL of ethanol was added0.2 mL of conc. HCl, and the mixture was refluxed for 2 days. Thesolvent was removed under reduced pressure, and the residue was purifiedby reverse-phase preparatory HPLC (26-53% acetonitrile+0.1%trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.)to give Compound 173 (26 mg, yield 20.0%). ¹H NMR (DMSO-d₆ 400 MHz): δ10.25 (s, 1H), 8.05 (m, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.28 (m, 4H), 7.08(d, J=7.2 Hz, 2H), 6.95 (d, J=18.8, 1H), 5.08 (m, 1H), 3.98 (m, 3H),3.62 (m, 3H), 3.01 (m, 1H), 2.13 (m, 2H), 1.31 (m, 3H); MS (ESI): m/z426.2 [M+1]⁺.

Example 174 Compound 174,6-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one

A mixture of 1-cyclohexyl-2-(thiophen-3-yl)ethanone (Intermediate 95)(176 mg, 0.56 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (140 mg,0.67 mmol), urea (100 mg, 1.68 mmol) and concentrated HCl solution (0.1mL) in absolute ethanol (5 mL) was reflux under N₂ overnight. Solventwas removed, and residue was purified by column chromatography andprep-HPLC to give Compound 174 (23 mg, yield: 9%) as a yellow solid. ¹HNMR (DMSO-d₆400 MHz): δ 10.25 (brs, 1H), 8.26 (s, 1H), 7.45 (dd, J=4.8,2.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.06 (d, J=1.6Hz, 1H), 6.85 (d, J=4.0 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.10-3.90 (m,2H), 1.90-1.40 (m, 7H), 1.35 (t, J=7.2 Hz, 3H), 1.20-1.00 (m, 3H). MS(ESI): m/z 444.2 [M+1]⁺.

Example 175 Compound 175,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((S)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one

To a mixture of (S)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone(Intermediate 93) (150 mg, 0.8 mmol),3-ethoxy-4-hydroxy-5-nitro-benzaldehyde (200 mg, 0.9 mmol), and urea(142 mg, 2.4 mmol) in absolute ethanol (3 mL) was added conc. HCl (onedrop). The mixture was refluxed under N₂ for 3 hrs. The reaction mixturewas concentrated in vacuo, and was purified by silica gel columnchromatography (PE:EtOAc=10:1 to PE:EtOAc=1:2) and prep-HPLC (0.1% TFAas additive) to give Compound 175 (30 mg, yield 9%). ¹H NMR (DMSO 400MHz): δ 10.28-10.16 (m, 1H), 7.65-7.45 (m, 0.5H), 7.40-7.17 (m, 4.5H),7.10-7.03 (m, 1.5H), 6.98-6.95 (m, 0.5H), 5.38-5.36 (s, 0.5H), 5.16-5.08(m, 0.5H), 4.30-4.20 (m, 0.5H), 4.10-3.85 (m, 3H), 3.62-3.53 (m, 0.5H),2.21-1.65 (m, 3.5H), 1.31-1.19 (m, 3H); MS (ESI): m/z 426.1 [M+1]⁺.

Example 176 Compound 176,4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((R)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one

To a mixture of (R)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone(Intermediate 94) (200 mg, 1.0 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (266 mg, 1.3 mmol), and urea (189mg, 3.2 mmol) in absolute ethanol (3 mL) was added conc. HCl (one drop).The mixture was refluxed under N₂ for 3.5 hrs. The reaction mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography (PE:EtOAc=10:1 to PE:EtOAc=1:2) and prep-HPLC (0.1% TFAas additive) to give Compound 176 (21 mg, yield 5%). ¹H NMR (DMSO 400MHz): δ 10.18 (s, 1H), 8.34 (s, 1H), 7.64 (s, 1H), 7.34-7.27 (m, 5H),7.16-7.10 (m, 1H), 7.07-7.04 (m, 1H), 5.38 (s, 1H), 4.26-4.21 (m, 1H),4.03-3.92 (m, 3H), 3.92-3.87 (m, 1H), 2.22-2.18 (m, 1H), 2.17-2.04 (m,2H), 2.00-1.95 (m, 1H), 1.32-1.22 (m, 3H); MS (ESI): m/z 426.0[M+1]⁺.

Example 177 Compound 177,5-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one

A mixture of urea (150 mg, 2.5 mmol),3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (104 mg, 0.49 mmol), CuCl (99 mg,1.0 mmol), BF₃-Et₂O (142 mg, 1.0 mmol) and AcOH (0.2 mL) in anhydrousTHF (10 mL) was stirred under refluxing under N₂ atmosphere for 0.5hour. Then 2-cyclohexyl-1-phenylethanone (Intermediate 96) (100 mg, 0.49mmol) in anhydrous THF (0.5 mL) was added and the reaction mixture wasrefluxed overnight. Followed a standard aqueous/EtOAc workup andpurified by prep-HPLC (0.1% TFA as additive) to give Compound 177 (20mg, yield 9%). ¹H NMR (CD₃OD 400 MHz): δ 7.74 (d, J=2.0 Hz, 1H),7.53-7.38 (m, 6H), 7.39 (d, J=2.0 Hz, 1H), 4.99 (s, 1H), 4.21 (q, J=7.2Hz, 1H), 2.35-2.28 (m, 1H), 1.69 (m, 1H), 1.64 (m, 1H), 1.55-1.47 (m,7H), 1.05-0.92 (m, 3H), 0.85-0.79 (m, 1H). MS (ESI): m/z 438.3 [M+1]⁺.

Example 178 Synthesis of Intermediates Intermediate 1: Synthesis of1-phenyl-2-(thiophen-2-yl)ethanone Step 1: Synthesis of2-(thiophen-2-yl)acetyl chloride

To a solution of 2-(thiophen-2-yl)acetic acid (2 g, 14 mmol) in DCM (50mL) was added dropwise SOCl₂ (0.5 mL), the mixture was heated at 50° C.overnight. The reaction mixture was concentrated under reduced pressureto give compound 2-(thiophen-2-yl)acetyl chloride, which was useddirectly in the next step without further purification.

Step 2: Synthesis of 1-phenyl-2-(thiophen-2-yl)ethanone (Intermediate 1)

To the solution of 2-(thiophen-2-yl)acetyl chloride (from above step) inbenzene (100 mL) was added AlCl₃ (3.88 g, 29.4 mmol) for 5 batches,after the completion of the addition, the mixture was heated to refluxfor 1 hour. The reaction mixture was poured into ice-water and extractedwith EtOAc (200 mL×3). The combined organic layer was washed with brine,dried over sodium sulfate, and concentrated under reduced pressure tothe crude product, which was purified by column chromatography(EtOAc:Petroleum=20:1) to give Intermediate 1 (600 mg, yield 21.2%).

Intermediate 2: Synthesis of 1-phenyl-2-(thiophen-3-yl)ethanone Step 1:Synthesis of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide

A mixture of 2-(thiophen-3-yl)acetic acid (2.0 g, 14.1 mmol),O,N-dimethyl-hydroxylamine(1.68 g, 16.9 mmol), EDCI (2.95 g, 15.5 mmol),HOBT (2.15 g, 15.5 mmol), and TEA (3.7 mL, 31 mmol) in anhydrous DCM (50mL) was stirred at room temperature under nitrogen for two hours. Thereaction mixture was diluted with CH₂Cl₂, and the organic layer waswashed with aqueous HCl solution (0.5 mol/L¹, 30 mL×2), saturated NaHCO₃(30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered, andconcentrated to give the crudeN-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (2.0 g, yield 76.6%).

Step 2: Synthesis of 1-phenyl-2-(thiophen-3-yl)ethanone (Intermediate 2)

To the solution of bromo-benzene (1.0 g, 6.36 mmol) in anhydrous THF (30mL) was added n-BuLi (5.9 mmol, 2.4 mL) at −78° C. under nitrogen, andthe mixture was stirred at −78° C. for further 20 min., a solution ofN-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (1 g, 5.4 mmol) inanhydrous THF (10 mL) was added. The resulting mixture was stirred at−78° C. under nitrogen for about 30 min., poured into NH₄Cl aqueoussolution, and extracted with EtOAc. The organic layers were washed withbrine, dried over sodium sulfate, concentrated, and purified by columnchromatograph (PE:EtOAc=20:1) to afford Intermediate 2 as a colorlessoil (600 mg, yield 55.0%).

Intermediate 3: Synthesis of 1-phenyl-2-(thiazol-2-yl)ethanone

To a solution of 2-methylthiazole (500 mg, 5.1 mmol) in anhydrous THF(10 mL) at −78° C. under nitrogen was added dropwise n-BuLi (2.5 mol/L,2.0 mL), after being stirred at this temperature for 1 hour, a solutionof ethyl benzoate (1.1 g, 7.3 mmol) in anhydrous THF (5 mL) was added,and the reaction mixture was stirred at room temperature overnight. WhenTLC (PE:EtOAc=7:1) indicated that the starting materials were consumed,water was added to quench the reaction, and the aqueous layer extractedwith EtOAc (10 mL×3). The combined organic layer was washed with brine(10 mL), dried over Na₂SO₄, filtered, concentrated, and purified bycolumn chromatography (PE:EtOAc=15:1) to afford Intermediate 3 as ayellow oil (170 mg, yield: 17.0%).

Intermediate 4: Synthesis of 1-phenyl-2-m-tolylethanone

Step 1:

A mixture of 2-m-tolylacetic acid (1 g, 6.7 mmol),N,O-dimethylhydroxylamine hydrochloride (654 mg, 6.7 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.7mmol), hydroxybenzotriazole (910 mg, 6.7 mmol) and triethylamine (3.38g, 33.5 mmol) in dichloromethane (30 mL) was stirred at room temperatureovernight. When TLC indicated that 2-m-tolylacetic acid was consumed,the reaction mixture was diluted with water (30 mL), and extracted withEtOAc (30 mL×3). The combined organic layer was dried over Na₂SO₄,concentrated in vacuo, and purified by column chromatography(PE:EtOAc=10:1) to afford N-methoxy-N-methyl-2-m-tolylacetamide (900 mg,yield 70%).

Step 2:

Under N₂, to a mixture of N-methoxy-N-methyl-2-m-tolylacetamide (500 mg,2.6 mmol) in anhydrous THF was added phenylmagnesium bromide (6.5 mL,6.5 mmol) at −78° C., and the mixture was stirred for 3 hours. When TLCindicated that the starting material was consumed, the reaction mixturewas diluted with EtOAc, washed with water and brine, concentrated, andpurified by column chromatography (PE:EtOAc=30:1) to give Intermediate 4(460 mg, yield 84.6%).

Intermediate 5: Synthesis of 2-(biphenyl-4-yl)-1-phenylethanone

Step 1:

A mixture of 2-(biphenyl-4-yl)acetic acid (1 g, 4.7 mmol),N,O-dimethylhydroxylamine hydrochloride (458 mg, 4.7 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (900 g, 4.7mmol), hydroxybenzotriazole (635 mg, 4.7 mmol), and triethylamine (1.42g, 14.1 mmol) in dichloromethane (30 mL) was stirred at room temperatureovernight. When TLC indicated that 2-(biphenyl-4-yl)acetic acid wasconsumed, the reaction mixture was diluted with water (30 mL), andextracted with EtOAc (30 mL×3). The combined organic layer was driedover Na₂SO₄, concentrated in vacuo, and purified by columnchromatography (PE:EtOAc=8:1) to afford2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide (1.0 g, yield 83%).

Step 2:

Under N₂, to a mixture of 2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide(500 mg, 1.96 mmol) in anhydrous THF was added phenylmagnesium bromide(5 mL, 5 mmol) at −78° C., and the mixture was stirred for 3 hours. WhenTLC indicated that the starting material was consumed, the reactionmixture was diluted with EtOAc, washed with water and brine,concentrated, and purified by column chromatography (PE:EtOAc=20:1) togive Intermediate 5 (430 mg, yield 80.7%).

Intermediate 6: Synthesis of 2-(3,4-dichlorophenyl)-1-phenylethanone

Step 1:

A mixture of 2-(3,4-dichlorophenyl)acetic acid (1 g, 4.9 mmol),N,O-dimethylhydroxylamine hydrochloride (480 mg, 4.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (940 mg, 4.9mmol), hydroxybenzotriazole (660 mg, 4.9 mmol), and triethylamine (2.5g, 25 mmol) in dichloromethane (30 mL) was stirred at room temperatureovernight. The reaction mixture was diluted with water (30 mL), andextracted with EtOAc (30 mL×3). The combined organic layers were driedover Na₂SO₄, concentrated in vacuo, and purified by columnchromatography (PE:EtOAc=10:1) to afford2-(3,4-dichlorophenyl)-N-methoxy-N-methylacetamide (880 mg, yield72.7%).

Step 2:

Under N₂, to a mixture of2-(3,4-dichlorophenyl)-N-methoxy-N-methylacetamide (440 mg, 1.8 mmol) inanhydrous THF was added phenylmagnesium bromide (4.4 mL, 4.4 mmol) at−78° C., and the mixture was stirred for 3 hours. When TLC indicatedthat the starting material was consumed, the reaction mixture wasdiluted with EtOAc, washed with water and brine, concentrated, andpurified by column chromatography (PE:EtOAc=20:1) to give Intermediate 6(400 mg, yield 85%).

Intermediate 7: Synthesis of 2-(3,4-dimethoxyphenyl)-1-phenylethanone

Step 1:

A mixture of 2-(3,4-dimethoxyphenyl)acetic acid (1 g, 5.1 mmol),N,O-dimethylhydroxylamine hydrochloride (480 mg, 5.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (978 mg, 5.1mmol), hydroxybenzotriazole (690 mg, 5.1 mmol) and triethylamine (2.57g, 25.5 mmol) in dichloromethane (30 mL) was stirred at room temperatureovernight. The reaction mixture was diluted with water (30 mL), andextracted with EtOAc (30 mL×3). The combined organic layer was driedover Na₂SO₄, concentrated in vacuo, and purified by columnchromatography (PE:EtOAc=8:1) to afford2-(3,4-dimethoxyphenyl)-N-methoxy-N-methylacetamide (370 mg, yield30.3%).

Step 2:

Under N₂, to a mixture of2-(3,4-dimethoxyphenyl)-N-methoxy-N-methylacetamide (200 mg, 0.84 mmol)in anhydrous THF was added phenylmagnesium bromide (2.1 mL, 2.1 mmol) at−78° C., and the mixture was stirred for 2 hours. When TLC indicatedthat the start material was consumed, the reaction mixture was dilutedwith EtOAc, washed with water and brine, concentrated, and purified bycolumn chromatography (PE:EtOAc=20:1) to give Intermediate 7 (130 mg,yield 61%).

Intermediate 8: Synthesis of 2-(4-bromophenyl)-1-phenylethanone

Prepared by the same two step synthesis described in the synthesis ofIntermediate 7, starting from 2-(4-bromophenyl)acetic acid.

Intermediate 9: Synthesis of 1-phenyl-2-o-tolylethanone

Step 1:

Followed procedure described in Step 1 of Intermediate 7, starting from2-o-tolylacetic acid, where crude material was purified by columnchromatography (PE:EtOAc=10:1) to affordN-methoxy-N-methyl-2-o-tolylacetamide (810 mg, yield 67.5%) as an oil.

Step 2:

Followed procedure described in Step 2 of Intermediate 7, where thecrude was purified by column chromatography (PE:EtOAc=30:1) to giveIntermediate 9 (200 mg, yield 45.9%) as an oil.

Intermediate 10: Synthesis of 2-(2-chlorophenyl)-1-phenylethanone

Step 1:

A mixture of 2-(2-chlorophenyl)acetic acid (1.0 g, 5.9 mmol),O,N-dimethyl-hydroxylamine (0.631 g, 6.3 mmol), EDCI (1.2 g, 6.3 mmol),HOBT (0.874 g, 6.3 mmol), and NMM (2.6 mL, 23.6 mmol) in anhydrousCH₂Cl₂ (20 mL) was stirred at room temperature for two hours undernitrogen. The reaction mixture was diluted with a mixture of CH₂Cl₂ andMeOH (v/v=10:1, 100 mL). The organic layer was washed with aqueous HCl(0.5 mol/L, 30 mL×2), saturated NaHCO₃ (30 mL×2) and brine (30 mL),dried over Na₂SO₄, filtered, and concentrated to give crude2-(2-chlorophenyl)-N-methoxy-N-methylacetamide (0.7 g, yield: 56.0%).

Step 2:

To a solution of 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide (0.51 g,2.4 mmol) in anhydrous THF (10 mL) cooled to −78° C., a solution ofphenylmagnesium bromide (1 mol/L, 3.5 mL) in THF was added. The reactionmixture was stirred at this temperature for five hours. TLC(PE:EtOAc=10:1) indicated that 50% of the starting materials wereconsumed. H₂O (10 mL) was added to quench the reaction, and the aqueouslayer extracted with EtOAc (10 mL×3). The combined organic layer waswashed with brine (10 mL), dried over Na₂SO₄, filtered, concentrated,and purified by column chromatography (PE:EtOAc=50:1) to affordIntermediate 10 as a colorless oil (80 mg, yield: 14.8%).

Intermediate 11: Synthesis of 3-(2-oxo-2-phenylethyl)benzonitrile

Step 1:

Followed procedure described in Step 1 of Intermediate 7, starting from2-(3-cyanophenyl)acetic acid, to afford2-(3-cyanophenyl)-N-methoxy-N-methylacetamide (340 mg, yield 53.6%).

Step 2:

Followed the procedure described in Step 2 of Intermediate 7, where themixture was stirred for 1 hour at −78° C. and at room temperature for 1hour. Workup and purification followed step 2 of intermediate 7, to giveIntermediate 11 (80 mg, yield 21.7%).

Intermediate 12: Synthesis of 2-(3,4-difluorophenyl)-1-phenylethanone

Step 1:

Followed the procedure described in Step 1 of Intermediate 7, startingfrom 2-(3,4-difluorophenyl)acetic acid, and purified by columnchromatography (PE:EtOAc=10:1) to afford2-(3,4-difluorophenyl)-N-methoxy-N-methylacetamide (840 mg, yield 70.1%)as an oil.

Step 2:

Followed the procedure described in Step 2 of Intermediate 7, where themixture was stirred for 3 hours. Purification was achieved by columnchromatography (PE:EtOAc=30:1) to give Intermediate 12 (250 mg, yield28.9%) as an oil.

Intermediate 13: Synthesis of 1-(3,5-dichlorophenyl)-2-phenylethanone

To a solution of 1-bromo-3,5-dichlorobenzene (1 g, 4.4 mmol) inanhydrous THF (10 mL) was added n-BuLi (339 mg, 5.3 mmol) at −78° C.After being stirred for 30 minutes, a solution ofN-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 ofIntermediate 4) (790 mg, 4.4 mmol) in THF (5 mL) was added, and themixture was stirred for 3 hours. When TLC indicated that startingmaterial was consumed, the reaction mixture was diluted with water (50mL), and extracted with EtOAc (20 mL×3). The combined organic layer wasdried over Na₂SO₄, concentrated in vacuum, and purified by columnchromatography (PE:EtOAc=50:1) to afford1-(3,5-dichlorophenyl)-2-phenylethanone (213 mg, yield 19.4%).

Intermediate 14: Synthesis of 1-(biphenyl-4-yl)-2-phenylethanone

To a solution of 4-bromobiphenyl (683 mg, 2.9 mmol) in anhydrous THF (5mL) was added n-BuLi (1.2 mL, 2.9 mmol) dropwise at −78° C. After beingstirred at the temperature for 0.5 h, a solution ofN-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 ofIntermediate 4) (500 mg, 2.8 mmol) in anhydrous THF (5 mL) was added viaa syringe, and the mixture was stirred at −78° C. for 2 h. The reactionwas quenched with saturated NH₄Cl aqueous solution, and extracted withEtOAc. The organic layer was dried over Na₂SO₄, concentrated in vacuo,and purified by column chromatography (PE:EtOAc=20:1) to give1-(biphenyl-4-yl)-2-phenylethanone (180 mg, yield 24%).

Intermediate 15: Synthesis of 4-(2-oxo-2-phenylethyl)benzonitrile

Step 1:

Followed the procedure described in Step 1 of Intermediate 5 startingfrom 2-(4-cyanophenyl)acetic acid to give the desired2-(4-cyanophenyl)-N-methoxy-N-methylacetamide (0.4 g, yield 63%).

Step 2:

Followed the procedure described in Step 2 of Intermediate 5, where themixture was stirred for 1 hour at −78° C. and then at room temperaturefor 1 hour. Workup and purification followed step 2 of intermediate 5,to give the desired compound, Intermediate 15, (70 mg, yield 16%).

Intermediate 16: Synthesis of1-(4-chloro-3-fluorophenyl)-2-phenylethanone

Prepared following the procedure described in Intermediate 13, startingfrom 4-bromo-1-chloro-2-fluorobenzene, where the crude product waspurified by column chromatography (PE:EtOAc=100:1) to affordIntermediate 16 (200 mg, yield 18.2%).

Intermediate 17: Synthesis of1-(3-chloro-4-fluorophenyl)-2-phenylethanone

Prepared following the procedure described in Intermediate 13, startingfrom 4-bromo-2-chloro-1-fluorobenzene, where the crude product waspurified by column chromatography (PE:EtOAc=100:1) to affordIntermediate 17 (110 mg, yield 20.0%).

Intermediate 18: Synthesis of 1-(3,5-difluorophenyl)-2-phenylethanone

Prepared following the procedure described in Intermediate 13, startingfrom 1-bromo-3,5-difluorobenzene, where the crude product was purifiedby column chromatography (PE:EtOAc=100:1) to afford Intermediate 18 (100mg, yield 10.3%).

Intermediate 19: Synthesis of 1-(3,4-dichlorophenyl)-2-phenylethanone

Prepared following the procedure described in Intermediate 13, startingfrom 4-bromo-1,2-dichlorobenzene, where the crude product was purifiedby column chromatography (PE:EtOAc=100:1) to afford Intermediate 19 (230mg, yield 42.4%).

Intermediate 20: Synthesis of1-(4-(methoxymethoxy)phenyl)-2-phenylethanone

Step 1:

To a solution of 4-bromophenol (1.0 g, 5.8 mmol) in anhydrous THF (10mL) was added NaH (60%, 254 mg, 6.4 mmol) at 0° C. After being stirredat the temperature for 0.5 h, MOM-Cl (698 mg, 8.7 mmol) was added to themixture. The mixture was stirred at 0° C. for 0.5 h, warmed to roomtemperature for 2 h, quenched with water, and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄, concentrated in vacuo, and purifiedby column chromatography (PE:EtOAc=50:1) to give1-bromo-4-(methoxymethoxy)benzene (1 g, yield 80%).

Step 2:

Prepared following the procedure described in Intermediate 13, where thecrude product was purified by column chromatography (PE:EtOAc=100:1) toafford Intermediate 20 (280 mg, yield 39%).

Intermediate 21: Synthesis of 1-(2,4-difluorophenyl)-2-phenylethanone

Prepared following the procedure described in Intermediate 14, startingfrom 1-bromo-2,4-difluorobenzene, where the crude product was purifiedby column chromatography (PE:EtOAc=50:1) to afford Intermediate 21 (250mg, yield 19%).

Intermediate 22: Synthesis of 1-(furan-3-yl)-2-phenylethanone

Step 1:

Followed step 1 of Intermediate 10, starting from furan-3-carboxylicacid to prepare the desired N-methoxy-N-methylfuran-3-carboxamide (913mg, yield: 65.9%).

Step 2:

A solution of N-methoxy-N-methylfuran-3-carboxamide (913 mg, 5.89 mmol)in anhydrous THF (10 mL) was cooled to −78° C. under nitrogen, and asolution of benzylmagnesium chloride in THF (2 mol/L, 3.53 mL) was addedthrough a syringe. The reaction mixture was stirred at this temperaturefor 5 hours. TLC (PE:EtOAc=5:1) indicated reaction was nearly complete,saturated NH₄Cl solution (20 mL) was added to quench the reaction, andthe aqueous layer was extracted with EtOAc (80 mL). The organic layerwas washed with brine (30 mL), dried over Na₂SO₄, filtered, andconcentrated to afford 1-(furan-3-yl)-2-phenylethanone as a yellow oil(696 mg, yield: 63.2%).

Intermediate 23: Synthesis of 3-(2-phenylacetyl)benzonitrile

Step 1:

Followed the procedure described in Intermediate 12, starting from1,3-dibromobenzene, where the crude product was purified by columnchromatography (PE:EtOAc=100:1) to give the desired1-(3-bromophenyl)-2-phenylethanone (520 mg, yield 47.7%).

Step 2:

The mixture of 1-(3-bromophenyl)-2-phenylethanone (200 mg, 0.73 mmol),zinc cyanide (128 mg, 1.09 mmol), andtetrakis(triphenylphosphine)palladium(84.3 mg, 0.073 mmol) inN,N-dimethylrormamide (4 mL) was degassed, and heated at 80° C. under N₂for 20 hours. The mixture was poured into water, and extracted withEtOAc. The combined organic layer was dried over Na₂SO₄, concentrated invacuo, and purified by column chromatography (PE:EtOAc=50:1) to afford3-(2-phenylacetyl)benzonitrile (130 mg, yield 80.7%).

Intermediate 24: Synthesis of 1-(2-fluorophenyl)-2-phenylethanone

Prepared from 1-bromo-2-fluorobenzene following the procedure describedin Intermediate 13, where the crude product was purified by columnchromatography (PE:EtOAc=100:1) to afford Intermediate 24 (300 mg, yield33.5%).

Intermediate 25: Synthesis of 1-(4-morpholinophenyl)-2-phenylethanone

Prepared from 4-(4-bromophenyl)morpholine following the proceduredescribed in Intermediate 14, where the crude product was purified bycolumn chromatography (PE:EtOAc=5:1) to afford Intermediate 25 (280 mg,yield 36%).

Intermediate 26: Synthesis of 1-phenyl-2-(pyrazin-2-yl)ethanone

To a mixture of diisopropyl-amine (1.29 g, 12.7 mmol) in anhydrous THF(10 mL) was added n-BuLi (2.5 M/L in hexane, 4.7 mL, 11.7 mmol) at −78°C., after being stirred for 30 minutes, a solution of 2-methylpyrazine(1 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at−78° C. for 30 minutes, a solution of methyl benzoate (1.4 g, 10.6 mmol)in THF (5 mL) was added, and the mixture was stirred at this temperaturefor 3 hours. When TLC indicated that the starting material was consumed,the reaction mixture was diluted with EtOAc, and the mixture was washedwith water and brine, and concentrated. The residue was purified bycolumn chromatography (PE:EtOAc=30:1) to give Intermediate 26 (700 mg,yield 33.3%).

Intermediate 27: Synthesis of 2-phenyl-1-(pyridin-2-yl)ethanone

A solution of ethyl picolinate (1.0 g, 6.62 mmol) in anhydroustetrahydrofuran (15 mL) was added benzylmagnesium chloride (3.64 mL,7.28 mmol) at −78° C. The mixture was stirred at −78° C. for 5 h, andpoured into saturated aqueous ammonium chloride solution (70 mL), andextracted with ethyl acetate (50 mL×2). The organic layer was washedwith brine (80 mL), and dried over anhydrous sodium sulfate. The solventwas removed, and the residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=10:1) to give Intermediate27 (700 mg, yield 53.6%).

Intermediate 28: Synthesis of 2-(biphenyl-3-yl)-1-phenylethanone

Step 1:

Followed the procedure described in Step 1 of Intermediate 7, startingfrom 2-(3-bromophenyl)acetic acid, and purified by column chromatography(PE:EtOAc=30:1) to afford 2-(3-bromophenyl)-N-methoxy-N-methylacetamide(2.1 g, yield 58.3%).

Step 2:

The mixture of 2-(3-bromophenyl)-N-methoxy-N-methylacetamide (2.0 g, 7.7mmol), phenylboronic acid (1.42 g, 11.6 mmol),1-1′-bis(diphenylphosphino)derrocene palladium dichloride (500 mg, 0.77mmol), and saturated aqueous sodium carbonate solution (1 mL) inN,N-dimethylformamide (20 mL) was heated at 80° C. under N₂ overnight.The mixture was poured into water, extracted with EA, dried over Na₂SO₄,concentrated in vacuo, and purified by column chromatography(PE:EtOAc=30:1-10:1) to afford2-(biphenyl-3-yl)-N-methoxy-N-methylacetamide (1.8 g, yield 94.7%).

Step 3:

Followed the procedure described in Step 2 of Intermediate 7, where themixture was stirred for 3 hours at −78° C. After workup, the crude waspurified by column chromatography (PE:EtOAc=30:1) to afford2-(biphenyl-3-yl)-1-phenylethanone (120 mg, yield 18.8%).

Intermediate 29: Synthesis of1-(benzo[d][1,3]dioxol-5-yl)-2-phenylethanone

Prepared from 4-bromobenzo[d][1,3]dioxole following the proceduredescribed in Intermediate 13, where the crude product was purified bycolumn chromatography (PE:EtOAc=20:1) to give Intermediate 29 (400 mg,yield 50.4%).

Intermediate 30: Synthesis of 4-(2-phenylacetyl)benzonitrile

Prepared from 4-bromobenzonitrile following the procedure described inIntermediate 14, (70 mg, yield 11%).

Intermediate 31: Synthesis of 2-phenyl-1-(pyridin-3-yl)ethanone

Step 1:

Followed the procedure described in Step 1 of Intermediate 7, startingfrom nicotinic acid where reaction was stirred at room temperature for 4h. The crude was purified by column chromatography (PE:EtOAc=2:1) toafford N-methoxy-N-methylnicotinamide (1.4 g, yield 52%).

Step 2:

Followed the procedure described in Step 2 of Intermediate 7 withN-methoxy-N-methylnicotinamide and benzylmagnesium chloride, where themixture was stirred for 3 hours. Purification was achieved by columnchromatography (PE:EtOAc=5:1) to give Intermediate 31 (110 mg, yield19%).

Intermediate 32: Synthesis of 3-ethoxy-5-fluoro-4-hydroxybenzaldehyde

Step 1:

To the solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (800 mg, 4.7mmol) in DCM (50 mL) was added AlCl₃ (680 mg, 5.1 mmol) portionwise, andat 0° C., pyridine (950 mg, 9.4 mmol) was added, and the resultingmixture was refluxed overnight. The reaction mixture was quenched withHCl ice-water solution, and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated under reduced pressure to give the3-fluoro-4,5-dihydroxybenzaldehyde as a pale solid (600 mg, yield 81%),which was used directly in the next step without further purification.

Step 2:

To the solution of 3-fluoro-4,5-dihydroxybenzaldehyde (200 mg, 1.28mmol) in DMF (50 mL) was added iodo-ethane (240 mg, 1.53 mmol) and K₂CO₃(210 mg, 1.53 mmol) at 0° C., and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into ice-watersolution, and extracted with EtOAc. The combined organic layers werewashed with brine, dried with Na₂SO₄, concentrated under reducedpressure, and purified by column chromatography to give3,4-diethoxy-5-fluorobenzaldehyde (100 mg, 36.8% yield).

Step 3:

To the solution of 3,4-diethoxy-5-fluorobenzaldehyde (300 mg, 1.4 mmol)in DCM (50 mL) was added AlCl₃ (207 mg, 1.55 mmol), and at 0° C.,pyridine (230 mg, 2.8 mmol) was added, and the resulting mixture wasrefluxed overnight. The reaction mixture was cooled to room temperature,poured into ice water solution, and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, concentrated underreduced pressure, and purified by column chromatography on silica gel togive 3-ethoxy-5-fluoro-4-hydroxybenzaldehyde (160 mg).

Intermediate 33: Synthesis of 2-(2-oxo-2-phenylethyl)benzonitrile

A suspension of NaH (1.4 g, 60% oil dispersion, 34 mmol) in drydimethoxyethane (10 mL) was heated at reflux, a solution of2-methylbenzonitrile (1 g, 8.5 mmol) in 5 mL of dimethoxyathane and asolution of ethyl benzoate (1.3 g, 8.5 mmol) in 10 mL of dimethoxyathanewere added. The resulting suspension was heated at reflux for 20 hours.The reaction mixture was cooled, and water was added cautiously. Theaqueous phase was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, concentrated, and purified by columnchromatography to give Intermediate 33 (380 mg, yield 20%) as a yellowsolid.

Intermediate 34: Synthesis of 3-ethoxy-5-formyl-2-hydroxybenzoic acid

Step 1:

A solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.0 g, 4.1 mmol)in DMF (10 mL) was cooled at 0° C., NaH (180 mg, 4.5 mmol) was added,and the mixture was stirred for 15 minutes. MOM-Cl (360 mg, 4.5 mmol)was added, and the mixture was warmed to room temperature in two hours.TLC (PE:EtOAc=5:1) indicated that the starting material was consumed.Ice water was added to quench the reaction, and aqueous layer wasextracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine (20 mL), dried over Na₂SO₄, filtered, concentrated, andpurified by column chromatograph to give3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (0.7 g, yield: 59.3%).

Step 2:

A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg,2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180°C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of thestarting material was consumed. The solvent was removed in vacuo, andthe residue was purified by column chromatograph to afford3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%).

Step 3:

A solution of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (230 mg, 1.2 mmol)in a mixture of EtOH (5 mL) and 2N aqueous NaOH (5 mL) was refluxed fortwo days. The reaction mixture was acidified to pH=1 with 1N HCl. Theaqueous layer was extracted with a mixture of EtOAc and MeOH (v/v=10:1,30 mL×3), and the combined organic layer was washed with brine, driedover Na₂SO₄, filtered, concentrated, and purified by columnchromatography to give Intermediate 34 (130 mg, yield: 51.6%).

Intermediate 35: Synthesis of 2-phenyl-1-(pyridin-4-yl)ethanone

Step 1:

Followed procedure described in Step 1 of Intermediate 7, starting fromisonicotinic acid, where the reaction was stirred at room temperaturefor 4 hours. The crude material was purified by column chromatography(PE:EtOAc=2:1) to afford N-methoxy-N-methylisonicotinamide (1.5 g, yield56%).

Step 2:

To a solution of N-methoxy-N-methylisonicotinamide (500 mg, 3.0 mmol) inanhydrous THF (10 mL) was added benzylmagnesium chloride (2 M in THF,1.8 mL, 3.6 mmol) drop wise at −78° C. After being stirred at thetemperature for 2 h, the reaction was quenched with NH₄Cl aqueoussolution, and extracted with EtOAc. The organic layer was dried overNa₂SO₄, concentrated in vacuo, and purified by column chromatography(PE:EtOAc=5:1) to give Intermediate 35 (60 mg, yield 10%).

Intermediate 36: Synthesis of 1-phenyl-2-(pyridin-4-yl)ethanone

Prepared following the procedure described in the synthesis ofIntermediate 26, with purification by column chromatography (petroleumether/ethyl acetate=6:1) to give Intermediate 36 (420 mg, yield 42.6%).

Intermediate 37: Synthesis of 3-ethoxy-5-formyl-2-hydroxybenzoic acid

Step 1:

A solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.0 g, 4.1 mmol)in DMF (10 mL) was cooled at 0° C., NaH (180 mg, 4.5 mmol) was added,and the mixture was stirred for 15 minutes. MOM-Cl (360 mg, 4.5 mmol)was added, and the mixture was warmed to room temperature in two hours.TLC (PE:EtOAc=5:1) indicated that the starting material was consumed.Ice water was added to quench the reaction, and aqueous layer wasextracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine (20 mL), dried over Na₂SO₄, filtered, concentrated, andpurified by column chromatography to give3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (0.7 g, yield: 59.3%).

Step 2:

A mixture of 3-bromo-5-ethoxy-4-(methoxymethoxy)benzaldehyde (600 mg,2.1 mmol) and CuCN (280 mg, 3.1 mmol) in DMF (10 mL) was heated at 180°C. for 4 hours. TLC (PE:EtOAc=1:1) indicated that the most of thestarting material was consumed. The solvent was removed in vacuo, andthe residue was purified by column chromatography to afford the3-ethoxy-5-formyl-2-hydroxybenzonitrile (200 mg, yield: 50.0%).

Step 3:

A solution of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (230 mg, 1.2 mmol)in a mixture of EtOH (5 mL) and 2 N aqueous NaOH (5 mL) was refluxed fortwo days. The reaction mixture was acidified to pH=1 with 1 N HCl. Theaqueous layer was extracted with a mixture of EtOAc and MeOH (v/v=10:1,30 mL×3), and the combined organic layer was washed with brine, driedover Na₂SO₄, filtered, concentrated, and purified by columnchromatograph to give Intermediate 37 (130 mg, yield: 51.6%).

Intermediate 38: Synthesis of 2-phenyl-1-(thiophen-2-yl)ethanone

Step 1:

A mixture of thiophene-2-carboxylic acid (2 g, 15.6 mmol),N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.6 mmol), EDCI (3.1 g,15.6 mmol), HOBT (2.4 g, 15.6 mmol), Et₃N (6.5 mL, 46.8 mmol) in DCM (30mL) was stirred at room temperature for 4 hours. The mixture wasconcentrated in vacuo and purified by column to giveN-methoxy-N-methylthiophene-2-carboxamide (1.8 g, yield 67%) as an oil.

Step 2:

The N-methoxy-N-methylthiophene-2-carboxamide (600 mg, 3.5 mol) wasconverted to Intermediate 38 following the procedure described in Step 2of Intermediate 35 to give Intermediate 38 (350 mg, 49%) as a whitesolid

Intermediate 39: Synthesis of 2-phenyl-1-(thiophen-3-yl)ethanone

Step 1:

Followed the procedure described in Step 1 of Intermediate 38 startingfrom thiophene-3-carboxylic acid to give the desiredN-methoxy-N-methylthiophene-3-carboxamide (1.7 g, yield 64%) as an oil.

Step 2:

The N-methoxy-N-methylthiophene-3-carboxamide (600 mg, 3.5 mol) wasconverted to Intermediate 39 following the procedure described in Step 2of Intermediate 35 to give the desired (1.7 g, yield 64%) as an oil.

Intermediate 40: Synthesis of1-(1-methyl-1H-imidazol-4-yl)-2-phenylethanone

Step 1:

Followed step 1 of Intermediate 10, starting from1-methyl-1H-imidazole-4-carboxylic acid to prepare the desiredN-methoxy-N,1-dimethyl-1H-imidazole-4-carboxamide (0.52 g, yield 38.0%).

Step 2:

Followed step 2 of Intermediate 35 to afford Intermediate 40 as a brownoil (130 mg, yield: 21.7%).

Intermediate 41: Synthesis of 1-(naphthalen-1-yl)-2-phenylethanone

Step 1:

Followed step 1 of Intermediate 10, starting from 1-naphthoic acid toprepare the desired N-methoxy-N-methyl-1-naphthamide (1.08 g, yield:86.2%).

Step 2:

Followed step 2 of Intermediate 35 to afford Intermediate 41 (354 mg,yield: 28.9%) as a solid.

Intermediate 42: Synthesis of 1-phenyl-2-(pyridin-3-yl)ethanone

Prepared following the procedure described in the synthesis ofIntermediate 26, with purification by column chromatography (petroleumether/ethyl acetate=15:1) to give Intermediate 42 (470 mg, yield 15.9%).

Intermediate 43: Synthesis of 1-(naphthalen-2-yl)-2-phenylethanone

Step 1:

Followed step 1 of Intermediate 10, starting from 2-naphthoic acid toprepare the desired N-methoxy-N-methyl-2-naphthamide (1.04 g, yield:83%).

Step 2:

Followed step 2 of Intermediate 35 to afford Intermediate 43 (270 mg,yield: 22.9%) as a solid.

Intermediate 44: Synthesis of2-(4-(dimethylamino)phenyl)-1-phenylethanone Step 1: Synthesis of2-(4-(dimethylamino)phenyl)-N-methoxy-N-methylacetamide

Followed the procedure described in Step 1 of Intermediate 7 startingfrom 2-(4-(dimethylamino)phenyl)acetic acid to give the desired2-(4-(dimethylamino)phenyl)-N-methoxy-N-methylacetamide (yield 72.6%).

Step 2: Synthesis of 2-(4-(dimethylamino)phenyl)-1-phenylethanone

Followed the procedure described in Step 2 of Intermediate 7, where themixture was stirred for 1 hour at −78° C. and at room temperature for 1hour. Workup according to step 2 of intermediate 7, followed by prepHPLC to give Intermediate 44 (yield 72.5%).

Intermediate 45: Synthesis of8-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde Step 1: Synthesisof 3,4-dihydroxy-5-nitrobenzaldehyde

To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (3 g, 15.2mmol) in acetic acid (3.1 mL) was added 40% hydrobromic acid (9.24 mL).The mixture was heated at 90° C. for 17 h. Reaction mixture was cooledand poured into ice water (100 mL), followed by a standard aqueous/EtOAcworkup and purified by column chromatography on silica gel (petroleumether/ethyl acetate=5:1) to give 3,4-dihydroxy-5-nitrobenzaldehyde (1.1g, yield 39.5%).

Step 2: Synthesis of8-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde

To a mixture of potassium fluoride dihydrate (2.573 g, 27.3 mmol), and3,4-dihydroxy-5-nitrobenzaldehyde (500 mg, 2.73 mmol) inN,N-dimethylformamide (20 mL) was added 1,2-dibromoethane (3.8 mL, 43.7mmol), and the mixture was heated at 130° C. for 17 h. The reactionmixture was quenched with water followed by a standard aqueous/EtOAcworkup and purified by column chromatography on silica gel (petroleumether/ethyl acetate=15:1) to give Intermediate 45 (350 mg, yield 62.1%).

Intermediate 46: Synthesis of 3-(isoxazol-4-yl)benzaldehyde Step 1:Synthesis of 4-iodoisoxazole

To a solution of NIS (23.0 g, 100 mmol) in TFA (200 mL) was addedisoxazole (6.9 g, 100 mmol) in one portion at room temperature and theresultant mixture was stirred for 18 h. The mixture was partitionedbetween PE (200 mL) and water (1000 mL). The organic phase was separatedand washed with saturated sodium bisulfate, dried with anhydrous Na₂SO₄,filtered and concentrated to give a yellow solid (1.2 g, 7%).

Step 2: Synthesis of 3-(isoxazol-4-yl)benzaldehyde

To a mixture of 4-iodoisoxazole (1 g, 5.13 mmol), 3-formylphenylboricacid (923 mg, 6.15 mmol) and sodium carbonate in DME/H₂O/Toluene/EtOH(15 mL, 3/1/10/6, V/V) was added Pd(PPh₃)₄ (200 mg). The mixture waspurged with N₂ for 30 min and heated to 80° C. for 3 h. The reactionmixture was cooled followed by a standard aqueous/EtOAc workup andpurified by prep-TLC (EA:PE=1:5) to give Intermediate 46 (12 mg, 1.5%).

Intermediate 47a and 47b: Synthesis of 5-formyl-2-hydroxybenzonitrile(Intermediate 47a) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b)

To a solution of 2-hydroxybenzonitrile (4.70 g, 41.6 mmol) in aceticacid (40 mL) was added hexamethylenetetraamine (8.7 g, 62.4 mmol) andthe mixture was heated to 120° C. for 2 h. The mixture was cooled toroom temperature, followed by a standard aqueous/EtOAc workup andpurified by silica gel column chromatography (PE:EA=1:1) to afford5-formyl-2-hydroxybenzonitrile (Intermediate 47a) as a white powder (540mg, 9%) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) as a whitepowder (1.17 g, 19%).

Intermediate 48: Synthesis of ethyl 2-ethoxy-4-formylbenzoate Step 1:Synthesis of ethyl 2-ethoxy-4-methylbenzoate

To a mixture of 2-hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol), K₂CO₃(18.9 g, 136.6 mmol) and acetone (50 mL) was added ethyl iodide (41.0 g,263.2 mmol). The mixture was stirred at room temperature for 3 days.After filtration, the organic layer was concentrated to afford ethyl2-ethoxy-4-methylbenzoate as colorless oil (5.7 g, 85%), which was useddirectly for next step.

Step 2: Synthesis of ethyl 4-(bromomethyl)-2-ethoxybenzoate

To a solution of ethyl 2-ethoxy-4-methylbenzoate (100 mg, 0.481 mmol) in2 mL of trifluoromethyl toluene was added NBS (94 mg, 0.529 mmol) andAIBN (10 mg) in portions. The mixture was heated to reflux and stirredfor 24 h. The reaction mixture was concentrated, diluted with 10 mL ofEA, washed with 5 mL of 4 N NaOH, 5 mL of brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford ethyl4-(bromomethyl)-2-ethoxybenzoate as brown oil (42 mg, 30%), which wasused for the next step directly.

Step 2: Synthesis of ethyl 2-ethoxy-4-formylbenzoate

To a solution of ethyl 4-(bromomethyl)-2-ethoxybenzoate (42 mg, 0.146mmol) in 20 mL of CHCl₃ was added hexamethylenetetramine (21 mg, 0.146mmol). The mixture was heated at 70° C. for 16 h. Filtration afforded 72mg of a light yellow solid. The solid was added to 2 mL of AcOH/H₂O(v/v=1/1) and the resultant mixture was heated at 90° C. for 16 h. Thereaction mixture was cooled, followed by a standard aqueous/EtOAc workupto afford ethyl 2-ethoxy-4-formylbenzoate (Intermediate 48) as a brownoil (32 mg, 86%), MS (ESI): m/z 223.1 [M+1]⁺.

Intermediate 49: 4-hydroxy-3-isopropoxy-5-nitrobenzaldehyde

To a mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (1.0 g, 5.46 mmol) indry DMF (10 mL) was added Cs₂CO₃ (3563 mg, 10.93 mmol), NaI (819 mg,5.46 mmol) and 2-bromopropane (1009 mg, 8.20 mmol) and the mixture wasstirred at 60° C. overnight. The mixture was cooled to room temperatureand added 1N HCl till pH=7, followed by a standard aqueous/EtOAc workup.The residue was purified by silica gel column chromatography(DCM:THF=20:1) to give Intermediate 49 as a yellow solid (230 mg,18.7%). ¹H NMR (DMSO-d₆ 500 MHz TMS): δ 9.86 (s, 1H), 8.08 (s, 1H), 7.65(s, 1H), 4.79 (m, 1H), 1.28 (d, J=6.5 Hz, 6H).

Intermediate 50: 3-ethoxy-4-hydroxy-5-(methylthio)benzaldehyde

To the solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.00 g, 4.08mmol) in pyridine (10 mL) was added Cu powder (0.52 g, 8.1 mmol) andmethyl disulfide (0.77 g, 8.2 mmol), the mixture was then heated at 90°C. overnight. The reaction mixture was filtered, and the solvent wasremoved under reduced pressure, the residue was poured into water, and 6N HCl (5 mL) was added, then the mixture was extracted with DCM (50mL×3), the combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gel column(PE:EA=5:1) to give Intermediate 50 (600 mg, yield 69%).

Intermediate 51: 3-ethoxy-5-formyl-2-hydroxybenzonitrile

A mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (200 mg, 0.82 mmol)and copper (I) cyanide in DMF (5 mL) was refluxed overnight. Thereaction mixture was diluted with water (20 mL), extracted with EtOAc,dried over Na₂SO₄, and concentrated under reduced pressure. Purified bycolumn chromatography on silica gel to afford Intermediate 51 (70 mg,yield 45%).

Intermediate 52: 2-phenyl-1-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethanoneStep 1: Synthesis of 1-(phenylsulfonyl)-1H-pyrrole

To a solution of 1H-pyrrole (5 g, 74.5 mmol) in DMF (50 mL) was addedNaH (4.5 g, 110 mmol) portionwise at 0° C., and the mixture was stirredat this temperature for 1 hour. Benzenesulfonyl chloride (19.4 g, 110mmol) was added, and the mixture was stirred at room temperatureovernight, followed by a standard aqueous/EtOAc workup and purified bycolumn chromatography (PE:EtOAc=100:1).

Step 2: Synthesis of2-phenyl-1-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethanone

Under N₂, a mixture of phenyl-acetyl chloride (1.5 g, 9.7 mmol) in1,2-dichloro-ethane (20 mL) was added AlCl₃ (2.24 g, 16.8 mmol) and thenstirred at room temperature for 15 minutes.1-(phenylsulfonyl)-1H-pyrrole (1.74 g, 8.4 mmol) was added. The mixturewas stirred at room temperature overnight, followed by a standardaqueous/EtOAc workup. Purified by column chromatography to afford theIntermediate 52 (1.4 g, yield 51.8%).

Intermediate 53: 1-(4-fluorophenyl)-2-(3-methoxyphenyl)ethanone

Step 1:

Followed the procedure described in Step 1 of Intermediate 7, startingfrom 2-(3-methoxyphenyl)acetic acid with a minor deviation wherereaction was stirred at room temperature for 4 h. Isolated yield ofN-methoxy-2-(3-methoxyphenyl)-N-methylacetamide was 1.5 g, yield 60% asan oil.

Step 2:

Followed the procedure described in Synthesis of Intermediate 14 usingN-methoxy-2-(3-methoxyphenyl)-N-methylacetamide and1-bromo-4-fluorobenzene to give desired Intermediate 53 (260 mg, 37%yield).

Intermediate 54: 1-(4-fluorophenyl)-2-(thiophen-3-yl)ethanone

Followed the procedure described in synthesis of Intermediate 14 usingN-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (prepared in Step 1 ofIntermediate 2) and 1-bromo-4-fluorobenzene to give Intermediate 54,(260 mg, 45%).

Intermediate 55: 5-formyl-2-hydroxy-3-nitrobenzoic acid

A solution of 5-formyl-2-hydroxybenzoic acid (2 g, 12.04 mmol) inconcentrated sulfuric acid (5 mL) was added a mixture of concentratednitric acid (1 mL) and concentrated sulfuric acid (1 mL) at 0° C. Theresulting suspension was stirred at 0° C. for 3 h, and poured into icewater (30 mL). The solid was collected by filtration, washed with water(30 mL), and dried in vacuo to give Intermediate 55 (2.2 g, yield86.6%).

Intermediate 56: 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone Step 1:Synthesis of nicotinoyl chloride

To a solution of nicotinic acid (2 g, 16.2 mmol) in anhydrous THF (30mL) was added SOCl₂ (2.4 mL, 32.5 mmol). After stirring at 80° C. for 2hours, the mixture was concentrated in vacuo.

Step 2: Synthesis of ethyl3-oxo-3-(pyridin-3-yl)-2-(thiophen-3-yl)propanoate:

To a solution of ethyl 2-(thiophen-3-yl)acetate (2.3 g, 16.2 mmol) inanhydrous THF (20 mL) was added LiHMDS (19.4 mL, 19.44 mmol) at −78° C.After stirring at that temperature for 0.5 h, a solution of nicotinoylchloride (2.8 g, 16.2 mmol) in anhydrous THF (10 mL) was added into thereaction mixture and stirred at −78° C. for 4 hours. The mixture wasquenched with NH₄Cl solution, extracted with EtOAc. The organic layerwas concentrated in vacuo and purified by column on silca gel (1.7 g,yield 38%).

Step 3: Synthesis of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone

To a solution of ethyl3-oxo-3-(pyridin-3-yl)-2-(thiophen-3-yl)propanoate (2 g, 7.26 mmol) inDMSO (20 mL) was added catalytic amount of brine (0.2 mL). The reactionmixture was heated at 160° C. for 2 h. The reaction mixture was cooledto room temperature, diluted with water, and extracted with EtOAc. Theorganic layer was concentrated in vacuo and purified by columnchromatography to afford Intermediate 56 (1 g, yield 68%).

Intermediate 57: 1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone

Followed same three step procedure described in Intermediate 56.

Step 1: Synthesis of 1-methyl-1H-pyrazole-4-carbonyl chloride

Started with 1-methyl-1H-pyrazole-4-carboxylic acid, and used tolueneinstead of THF.

Step 2: Synthesis of ethyl3-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2-(thiophen-3-yl)propanoate

Used crude from step 1 and ethyl 2-(thiophen-3-yl)acetate. Afterstirring at −78° C., the reaction was warmed to room temperature andstirred overnight.

Step 3: Synthesis of1-(1-methyl-1H-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone

Reaction mix stirred at 180° C. for 2 hours. Purified by columnchromatography (PE:EtOAc=10:1) to give Intermediate 57 (160 mg, yield61.8%).

Intermediate 58: 1-(1-methyl-1H-pyrazol-3-yl)-2-(thiophen-3-yl)ethanone

Followed same three step procedure described in Intermediate 56.

Step 1: Synthesis of 1-methyl-1H-pyrazole-3-carbonyl chloride

Started with 1-methyl-1H-pyrazole-3-carboxylic acid, and used tolueneinstead of THF.

Step 2: Synthesis of ethyl3-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2-(thiophen-3-yl)propanoate

Used crude from step 1 and ethyl 2-(thiophen-3-yl)acetate. Purified bysilica gel column chromatography (PE:EtOAc=10:1) (1.8 g, 2-step yield82%).

Step 3: Synthesis of1-(1-methyl-1H-pyrazol-3-yl)-2-(thiophen-3-yl)ethanone

Purified by column chromatography (PE:EtOAc=8:1) to give Intermediate 58(960 mg, yield 74%).

Intermediate 59: 3-chloro-4-hydroxy-5-nitrobenzaldehyde

To a solution of 3-chloro-4-hydroxybenzaldehyde (400 mg, 2.55 mmol) inacetic acid (5 mL) was added concentrated nitric acid (0.1 mL) and at 0°C., the resulting suspension was stirred at 25° C. for 6 h. The mixturewas poured into ice water; the solid was collected by filtration, washedwith water (30 mL) and dried in vacuo to give Intermediate 59 (300 mg,58.4%).

Intermediate 60: 1-(3-chloro-5-fluorophenyl)-2-phenylethanone Step 1:Synthesis of 3-chloro-5-fluoro-N-methoxy-N-methylbenzamide

Followed the procedure described in Step 1 of Intermediate 7, startingfrom 3-chloro-5-fluorobenzoic acid.

Step 2: Synthesis of 1-(3-chloro-5-fluorophenyl)-2-phenylethanone

Followed the procedure described in Step 2 of Intermediate 22 using3-chloro-5-fluoro-N-methoxy-N-methylbenzamide and benzylmagnesiumchloride, with a purification by column chromatography to give desiredIntermediate 60 (850 mg, 75%)

Intermediate 61: 5-formyl-2-hydroxy-3-nitrobenzonitrile Step 1:Synthesis of 5-formyl-2-hydroxybenzonitrile

To a mixture of 3-bromo-4-hydroxybenzaldehyde (1.00 g, 4.97 mmol) in DMF(10 mL) was added cuprous cyanide (660 mg, 7.46 mmol). The mixture washeated at 180° C. for 8 hours. The solution was filtered off andpurified by chromatography on silica gel (PE/EtOAc=8:1) (210 mg, 29%).

Step 2: Synthesis of 5-formyl-2-hydroxy-3-nitrobenzonitrile

To a solution of 5-formyl-2-hydroxybenzonitrile (200 mg, 1.36 mmol) inacetic acid (4 mL) was added slowly concentrated nitric acid (0.8 mL) at0° C. The resulting mixture was stirred for 5 hours. Then the mixturewas poured into ice-water (40 mL) and ethyl acetate (100 mL). Organicwas washed with brine (80 mL), dried over sodium sulfate and evaporatedin vacuo, followed by column chromatography (petroleum ether/ethylacetate=3:1) to give Intermediate 61 (250 mg, yield 96%).

Intermediate 62: 3-ethoxy-5-formyl-2-hydroxybenzoic acid

A mixture of 3-ethoxy-5-formyl-2-hydroxybenzonitrile (Intermediate 51)(500 mg, 2.6 mmol) in NaOH aqueous solution (8 M, 10 mL) and EtOH (10mL) was refluxed for 2 days. The mixture was acidified with HCl solutionto pH=4-5 and extracted with EtOAc. The organic layer was dried overNa₂SO₄ and concentrated to give Intermediate 62 (450 mg, yield 82%).

Intermediate 63: 3-fluoro-4-hydroxy-5-nitrobenzaldehyde

Followed procedure described for Intermediate 59, starting with3-fluoro-4-hydroxybenzaldehyde. Desired product isolated in 53% yield.

Intermediate 64: 1-(3-hydroxyphenyl)-2-phenylethanone Step 1: Synthesisof 3-hydroxy-N-methoxy-N-methylbenzamide

Followed the procedure described in Step 1 of Intermediate 7, startingfrom 3-hydroxybenzoic acid, where reaction was run for 6 h at 30° C.instead of room temperature overnight.

Step 2: Synthesis of 1-(3-chloro-5-fluorophenyl)-2-phenylethanone

Followed the procedure described in Step 2 of Intermediate 22, with apurification by column chromatography (petroleum ether/ethylacetate=10:1) to give Intermediate 64 (260 mg, yield 55.4%).

Intermediate 65: 4-hydroxy-3-nitro-5-propoxybenzaldehyde Step 1:Synthesis of 3,4-dihydroxy-5-nitrobenzaldehyde

To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (2.0 g, 10.15mmol) in anhydrous CH₂Cl₂ (10 mL) was added boron tribromide (4 mL) at0° C. Reaction was warmed to room temperature and stirred for 2 hourunder N₂. Followed a standard aqueous/EtOAc workup. The residue waspurified by silica gel column chromatography (1.2 mg, yield: 64.6%).

Step 2: Synthesis of 3-nitro-4,5-dipropoxybenzaldehyde

To a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (400 mg, 2.185 mmol)in DMF (5 mL) was added K₂CO₃ (603 mg, 4.37 mmol) and 1-bromopropane(0.5 mL, excess), and the reaction was stirred at 80° C. overnight.Ethyl acetate (100 mL) was added and was washed with 2N aqueous HClsolution (20 mL×1), brine (20 mL×3), dried over Na₂SO₄, filtered,concentrated. The residue was purified by column chromatography (192 mg,yield: 32.91%).

Step 3: Synthesis of 4-hydroxy-3-nitro-5-propoxybenzaldehyde

To a solution of 3-nitro-4,5-dipropoxybenzaldehyde (153 mg, 0.573 mmol)in anhydrous CH₂Cl₂ (5 mL) was added anhydrous AlCl₃ (151 mg, 1.15 mmol)at 0° C., after the addition, the reaction mixture was stirred at 50° C.for 1 hour. The reaction was quenched by water (20 mL), and the mixturewas acidified with 2N aqueous HCl solution (20 mL), followed by astandard aqueous/EtOAc workup. Purification by column chromatographygave Intermediate 65 (126 mg, yield: 97.7%).

Intermediate 66: 1-(pyrazin-2-yl)-2-(thiophen-3-yl)ethanone

Followed same three step procedure described in Intermediate 56.

Step 1: Synthesis of pyrazine-2-carbonyl chloride

Started with 1 pyrazine-2-carboxylic acid, and used toluene instead ofTHF.

Step 2: Synthesis of ethyl3-oxo-3-(pyrazin-2-yl)-2-(thiophen-3-yl)propanoate

Used crude from step 1 and ethyl 2-(thiophen-3-yl)acetate.

Step 3: Synthesis of 1-(pyrazin-2-yl)-2-(thiophen-3-yl)ethanone

Reaction was run at 180° C. for 6 hours. Purified by columnchromatography (PE:EtOAc=8:1) to give Intermediate 66 (30 mg, yield6.1%).

Intermediate 67: 2-phenyl-1-(quinolin-6-yl)ethanone

Followed same three step procedure described in Intermediate 56.

Step 1: Synthesis of quinoline-6-carbonyl chloride

Started with quinoline-6-carboxylic acid, and used toluene instead ofTHF.

Step 2: Synthesis of ethyl 3-oxo-2-phenyl-3-(quinolin-6-yl)propanoate

Used crude from step 1 and ethyl 2-phenylacetate.

Step 3: Synthesis of 2-phenyl-1-(quinolin-6-yl)ethanone

Reaction run at 180° C. for 6 hours. Purified by column chromatography(PE:EtOAc=5:1) to give Intermediate 67 (100 mg, 35.2%).

Intermediate 68: 1-(isoquinolin-6-yl)-2-phenylethanone Step 1: Synthesisof isoquinoline-6-carbonitrile

Under N₂, a mixture of 6-bromoisoquinoline (400 mg, 1.9 mmol), Zn(CN)₂(446 mg, 3.8 mmol) and Pd(PPh₃)₄ (40 mg) in DMF (20 mL) was stirred at100° C. for 1 hour. Cooled the mixture to room temperature and dissolvedin water. Followed standard aqueous/EtOAc workup and purified by columnchromatography (PE:EtOAc=10:1).

Step 2: Synthesis of isoquinoline-6-carboxylic acid

A mixture of isoquinoline-6-carbonitrile (250 mg, 1.6 mmol) and aqueousKOH (5 mL, 2M) was stirred at 150° C. for 4 hours. The mixture wasconcentrated in vacuo and used in the next step directly.

Step 3, 4, and 5

Followed same three step procedure described in Intermediate 67 to giveIntermediate 68, 1-(isoquinolin-6-yl)-2-phenylethanone.

Intermediate 69: 2-(3-methoxyphenyl)-1-(pyridin-3-yl)ethanone

Followed the three step procedure described in Intermediate 56.

Step 1: Synthesis of nicotinoyl chloride

See step 1, Intermediate 56.

Step 2: Synthesis of methyl2-(3-methoxyphenyl)-3-oxo-3-(pyridin-3-yl)propanoate

Used crude from step 1 and methyl 2-(3-methoxyphenyl)acetate.

Step 3: Synthesis of 2-(3-methoxyphenyl)-1-(pyridin-3-yl)ethanone

Reaction run at 180° C. for 1 hours. Used crude after workup.

Intermediate 70: 1-(pyridin-4-yl)-2-(thiophen-3-yl)ethanone

Followed the three step procedure described in Intermediate 56.

Step 1: Synthesis of isonicotinoyl chloride

Started with isonicotinic acid, and used toluene instead of THF.

Step 2: Synthesis of ethyl3-oxo-3-(pyridin-4-yl)-2-(thiophen-3-yl)propanoate

Used crude from step 1 and ethyl 2-(thiophen-3-yl)acetate.

Step 3: Synthesis of 1-(pyridin-4-yl)-2-(thiophen-3-yl)ethanone

Reaction run at 150° C. for 3 hours. Purified by silica gel columnchromatography (petroleum ether/ethyl acetate=10:1) to give Intermediate70 (900 mg, yield 100%).

Intermediate 71: 4-hydroxy-3-(2-hydroxyethoxy)-5-nitrobenzaldehyde Step1: Synthesis of 3-(2-hydroxyethoxy)-4-methoxybenzaldehyde

Followed procedure described in Intermediate 65, step 2 starting from3-hydroxy-4-methoxybenzaldehyde and 2-bromoethanol, using crude materialfor next step.

Step 2: Synthesis of 4-hydroxy-3-(2-hydroxyethoxyl)benzaldehyde

Followed procedure described in Intermediate 65, step 3 where reactionwas refluxed for 2 days.

Step 3: Synthesis of 4-hydroxy-3-(2-hydroxyethoxy)-5-nitrobenzaldehyde

Followed procedure described for Intermediate 61, starting from the4-hydroxy-3-(2-hydroxyethoxyl)benzaldehyde to give desired product,Intermediate 71.

Intermediate 72: 1-(1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)ethanoneStep 1: Synthesis of ethyl3-(1-methyl-1H-pyrazol-5-yl)-3-oxo-2-(thiophen-3-yl)propanoate

To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (300 mg, 2.4mmol) in DMF (7 mL) was added CDI (372 mg, 2.6 mmol), and the reactionmixture was heated to 50° C. for two hours. Then the mixture was cooledto −5° C., a solution of ethyl 2-(thiophen-3-yl)acetate (444 mg, 2.6mmol) in DMF (1 mL) was added to the mixture and NaH (330 mg, 8.2 mmol)was added in portions. The mixture was stirred at 0° C. for 10 minutes,then warmed to room temperature and stirred for 1 hour. Ice water wasadded, followed by a standard aqueous/EtOAc workup. Crude was purifiedby column chromatography (PE:EtOAc=5:1) (150 mg, yield: 22.7%).

Step 2: Synthesis of1-(1-methyl-1H-pyrazol-5-yl)-2-(thiophen-3-yl)ethanone

Followed Step 3 of Intermediate 56 starting with the above from Step 1,with purification by column chromatography (PE:EtOAc=10:1) to giveIntermediate 72 (90 mg, yield: 81.1%).

Intermediate 73: 4-formyl-2-nitrobenzoic acid Step 1: Synthesis of4-formyl-2-nitrobenzonitrile

A mixture of 4-bromo-3-nitrobenzaldehyde (1 g, 4.35 mmol) indimethylformamide (10 mL) was added cuprous cyanide (584.8 mg, 6.53mmol). The resultant solution was stirred at 160° C. for 5 hours. Aftercooling, a standard aqueous/EtOAc workup was followed. Purified bysilica gel column chromatography to give product (430 mg, yield 56.1%).

Step 2: Synthesis of 4-formyl-2-nitrobenzoic acid

A mixture of 4-formyl-2-nitrobenzonitrile (150 mg, 0.85 mmol) in conc.sulfuric acid (2 mL) and water (4 mL) was heated at 100° C. for 13hours. Followed standard aqueous/EtOAc workup to give Intermediate 73.

Intermediate 74: 2-(3-ethylphenyl)-1-phenylethanone Step 1: Synthesis ofethyl 2-(3-vinylphenyl)acetate

To a mixture of ethyl 2-(3-bromophenyl)acetate (1.5 g, 6.1 mmol) inanhydrous DMF (15 mL) was added tributyl(vinyl)stannane (2.1 mL, 7.4mmol) and tetrakis(triphenylphosphine) palladium (400 mg, 0.5 mmol)under nitrogen atmosphere. The resulting mixture was stirred at 110° C.for 8 hours. Followed a standard aqueous/EtOAc workup. Purified bysilica gel column chromatography (petroleum:ether/ethyl acetate=15:1)(640 mg, yield 54%).

Step 2: Synthesis of ethyl 2-(3-ethylphenyl)acetate

To a solution of ethyl 2-(3-vinylphenyl)acetate (640 mg, 3.6 mmol) inethanol (10 mL) was added 10% of Pd/C (100 mg) and stirred at 30° C.under hydrogen atmosphere (15 psi) for 7 hours. Then the solution wasfiltered and the solvent was removed in vacuo (500 mg, yield 77%).

Step 3: Synthesis of 2-(3-ethylphenyl)acetic acid

To a mixture of the preceding compound (400 mg, 2.1 mmol) in ethanol (2mL) was added sodium hydroxide (166 mg, 4.1 mmol) and water (2 mL). Theresulting mixture was stirred at 26° C. for 6 hours. The reactionmixture was acidified with 2N of HCl to pH=5. Followed a standardaqueous/EtOAc workup procedure to give crude product (400.0 mg).

Step 4: Synthesis of 2-(3-ethylphenyl)-N-methoxy-N-methylacetamide

Followed Step 1 of Intermediate 7, where reaction was run for 7 h at 30°C.

Step 5: Synthesis of 2-(3-ethylphenyl)-1-phenylethanone

Followed Step 2 of Intermediate 10, to give Intermediate 74 (80 mg,yield: 14.8%).

Intermediate 75: methyl 2-chloro-4-formylbenzoate Step 1: Synthesis of3-chloro-4-(methoxycarbonyl)benzoic acid

To a mixture of 3-amino-4-(methoxycarbonyl)benzoic acid (781 mg, 4.0mmol) suspended in acetic acid (10 mL) and conc. HCl (10 mL) was addedaq. NaNO₂ (276 mg, 4.0 mmol, 5 mL) at 0° C. The resulting mixture wasstirred for 30 minutes. CuCl (400 mg, 8.0 mmol) in 10 mL of conc. HCl.was added to the mixture at 0° C. The resulting mixture was stirred at30° C. for 6 hours. Followed a standard aqueous/EtOAc workup procedure(800 mg, yield 93%).

Step 2: Synthesis of methyl 2-chloro-4-(hydroxymethyl)benzoate

To a solution of 3-chloro-4-(methoxycarbonyl)benzoic acid (400 mg, 1.9mmol) in anhydrous THF (15 mL) was added Borane methyl sulfide complex(10 M, 0.56 mL, 5.6 mmol). The resulting solution was heated at 76° C.for 6 hours. After being cooled, the mixture was slowly poured intowater (40 mL) at −10° C., then followed a standard aqueous/EtOAc workupprocedure to give crude product (350 mg, yield 94%).

Step 3: Synthesis of methyl 2-chloro-4-formylbenzoate

A mixture of methyl 2-chloro-4-(hydroxymethyl)benzoate (350 mg, 1.7mmol) in and manganese oxide (756 mg, 30.9 mmol) in dichloromethane (10mL) was stirred at 27° C. for 6 hours. The mixture was filtered andevaporated in vacuo to give Intermediate 75 (210 mg, 61%).

Intermediate 76:4-ethoxy-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbaldehyde Step 1:Synthesis of ethyl 4-bromo-3,5-diethoxybenzoate

A mixture of 4-bromo-3,5-dihydroxybenzoic acid (2.0 g, 8.6 mmol), EtI(6.7 g, 43.0 mmol) and K₂CO₃ (5.9 g, 43.0 mmol) in DMF (20 mL) wasstirred at 50° C. overnight. Followed standard aqueous/EtOAc workup (2.5g, yield 93%).

Step 2: Synthesis of ethyl 4-cyano-3,5-diethoxybenzoate

Followed Step 1 of Intermediate 68 where reaction was stirred overnightinstead of 1 hour, and crude was purified by column chromatography(PE:EtOAc=15:1) (1.0 g, yield 60%).

Step 3: Synthesis of 2,6-diethoxyterephthalic acid

A mixture of ethyl 4-cyano-3,5-diethoxybenzoate (1.0 g, 3.8 mmol) andKOH (5.0 g, 89.3 mmol) in water (30 mL) was stirred at 130° C.overnight. The mixture was acidified with aqueous HCl (2M) until pH=5.Solvent removed in vacuo and used for next step directly without furtherpurification.

Step 4: Synthesis of diethyl 2,6-diethoxyterephthalate

Followed Step 1 of Intermediate 76 where crude was purified by columnchromatography on silica gel (PE:EtOAc=10:1) to give 600 mg, yield 50%.

Step 5: Synthesis of ethyl4-ethoxy-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate

A mixture of diethyl 2,6-diethoxyterephthalate (300 mg, 0.97 mmol) andNH₂OH HCl salt (47 mg, 6.8 mmol) in PPA (1 mL) was stirred at 70° C.under N₂ atmosphere overnight. A standard aqueous/EtOAc workup procedurewas followed. The residue was purified by column chromatography onsilica gel (PE:EtOAc=10:1) to give 80 mg of product, yield 33%.

Step 6: Synthesis of 4-ethoxy-6-(hydroxymethyl)benzo[d]oxazol-2(3H)-one

To a solution of above from step 5 (140 mg, 0.56 mmol) in DCM (10 mL)and THF (5 mL) was added DIBAL-H (1 M, 2 mL, 2.0 mmol) at −78° C. underN₂ atmosphere and the reaction mixture was stirred at the sametemperature for 2 hours. A standard aqueous/EtOAc workup procedure wasfollowed, and material was used crude.

Step 7: Synthesis of4-ethoxy-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbaldehyde

A mixture of above from step 6 (137 mg) and MnO₂ (500 mg) in DCM (20 mL)was stirred at 50° C. overnight. The mixture was filtered and thefiltrate was concentrated under reduced pressure and purified by columnchromatography on silica gel (PE:EtOAc=8:1) to give 80 mg, yield 59%.

Intermediate 77: Synthesis of 3-bromo-5-fluoro-4-hydroxybenzaldehyde

To a mixture of 3-fluoro-4-hydroxybenzaldehyde (700 mg, 5.0 mmol) inacetic acid (5 mL) and dichloromethane (5 mL) was added bromine (0.5 mL,9.8 mmol) at 0° C. The resulting mixture was stirred at 20° C. for 7hours and then it was poured into water (50 mL), filtrated, the filteredcake was dried to give Intermediate 77 (700 mg, yield 64%).

Intermediate 78: Synthesis of methyl 2-ethoxy-4-formyl-6-nitrobenzoateStep 1: Synthesis of 2-ethoxy-4-formyl-6-nitrophenyltrifluoromethanesulfonate

To a solution of 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (5.0 g, 23.7mmol) and triethylamine (11.9 g, 118.5 mmol) in anhydrous DCM (70 mL)was added trifluoromethanesulfonic anhydride (10.0 g, 35.6 mmol)dropwise at 0° C. The mixture was stirred under N₂ atmosphere for 1 hr.The reaction was quenched with water (100 mL), followed by a standardaqueous/EtOAc workup. The residue was purified by silica gel columnchromatography (PE:EtOAc=50:1 to PE:EtOAc=5:1) (6.2 g, yield 76%).

Step 2: Synthesis of 3-ethoxy-4-iodo-5-nitrobenzaldehyde

To a solution of 2-ethoxy-4-formyl-6-nitrophenyltrifluoromethanesulfonate (4.7 g, 13.7 mmol) in DMSO (10 mL) was addedsodium iodide (6.2 g, 41.1 mmol). The mixture was stirred under N₂atmosphere at 3˜10° C. overnight. EtOAc/aqueous workup. Purified bysilica gel column chromatography (PE:EtOAc=50:1 to PE:EtOAc=10:1) (4.0g, yield 91%).

Step 3: Synthesis of methyl 2-ethoxy-4-formyl-6-nitrobenzoate

To a solution of the above (4.0 g, 12.5 mmol) in DMF (30 mL) was addedPd(OAc)₂ (40 mg, 0.2 mmol), dppf (50 mg, 0.09 mmol), triethylamine (3.8g, 37.4 mmol) and methanol (20 mL, excess). The mixture was stirredunder CO atmosphere (30 psi) at 75° C. overnight. The reaction mixturewas filtered and concentrated under reduced pressure. Purified by silicagel column chromatography (PE:EtOAc=20:1 to PE:EtOAc=5:1) to giveIntermediate 78 (1.5 g, yield 48%).

Intermediate 79: Synthesis of4-hydroxy-3-nitro-5-(trifluoromethyl)benzaldehyde

To a mixture of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (200 mg, 1.05mmol) suspended in conc. sulfuric acid (2 mL) was added conc. nitricacid (0.1 mL) slowly at 0° C. for 5 min. The mixture was poured into icewater (30 mL), isolated by filtration, dried to give Intermediate 78(210 mg, yield 85%) as yellow solid.

Intermediate 80: 4-hydroxy-3-(2-methoxyethoxy)-5-nitrobenzaldehyde Step1: Synthesis of 4-methoxy-3-(2-methoxyethoxyl)benzaldehyde

Followed the procedure described in Step 2 of Intermediate 65 startingfrom 3-hydroxy-4-methoxybenzaldehyde, isolated 2.4 g, yield 89%.

Step 2: Synthesis of 4-hydroxy-3-(2-methoxyethoxyl)benzaldehyde

Followed the procedure described in Step 3 of Intermediate 65, where thereaction was refluxed for 2 days. Isolated 900 mg, yield 97% aftercolumn chromatography (PE:EtOAc=10:1).

Step 3: Synthesis of 4-hydroxy-3-(2-methoxyethoxy)-5-nitrobenzaldehyde

Followed the procedure described in Step 2 of Intermediate 61, wherecrude was taken on without purification. Product (450 mg, 92%) wasisolated as a yellow solid.

Intermediate 81:4-(tert-butyldimethylsilyloxy)-3-nitro-5-propylbenzaldehyde Step 1:Synthesis of ethyl 4-(allyloxy)benzoate

To a mixture of ethyl 4-hydroxybenzoate (10.0 g, 60.0 mmol) in acetone(100 mL) was added K₂CO₃ (33.0 g, 239.1 mmol) at 10° C.; stirred for 0.5hour. Then 3-bromo-propene (8.0 g, 66.0 mmol) was added dropwise and thereaction mixture was stirred at 10° C. for 5 hours. The resultingmixture was filtered and the filtrate was concentrated under reducedpressure to give product (12.0 g, 96%).

Step 2: Synthesis of ethyl 3-allyl-4-hydroxybenzoate

A mixture of the above crude (10.0 g, 48.5 mmol) in Ph₂O (50 mL) wasstirred at 200° C. for 5 hours. Cooled reaction and purified by columnchromatography on silica gel (PE:EtOAc=50:1) to give product (6.7 g,yield 67%).

Step 3: Synthesis of ethyl 4-hydroxy-3-propylbenzoate

Followed Step 2 of Intermediate 74, gave 5.5 g, yield 81% of product.

Step 4: Synthesis of ethyl 4-hydroxy-3-nitro-5-propylbenzoate

Followed the procedure described in Step 2 of Intermediate 61, wherereaction was complete in 10 min. and crude was taken on withoutpurification. Product (1.3 g, yield 97%) was isolated as a yellow oil.

Step 5: Synthesis of ethyl4-(tert-butyldimethylsilyloxy)-3-nitro-5-propylbenzoate

A mixture of ethyl 4-hydroxy-3-nitro-5-propylbenzoate (1.5 g, 5.9 mmol),TBSCl (1.3 g, 8.9 mmol) and imidazole (800 mg, 11.8 mmol) in DMF (20 mL)was stirred at 30° C. overnight. A standard aqueous/EtOAc workup wasfollowed by a purification by column chromatography (PE:EtOAc=15:1) togive product as a yellow oil (1.9 g, yield 86%).

Step 6: Synthesis of(4-(tert-butyldimethylsilyloxy)-3-nitro-5-propylphenyl)methanol

Followed Step 6 of Intermediate 76 to give crude product as a yellow oil(200 mg, yield 75%).

Step 7: Synthesis of4-(tert-butyldimethylsilyloxy)-3-nitro-5-propylbenzaldehyde

Followed Step 7 of Intermediate 76 where reaction was stirred at 30° C.overnight. Product was isolated after workup and was taken on crude as ayellow oil (100 mg, yield 50%).

Intermediate 82: methyl 4-formyl-2-(trifluoromethyl)benzoate Step 1:Synthesis of 4-formyl-2-(trifluoromethyl)phenyltrifluoromethanesulfonate

To a mixture of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (500 mg, 2.7mmol), TEA (805 mg, 8.0 mmol) in anhydrous DCM (10 mL) was added Tf₂O(820 mg, 2.9 mmol) drop wise at 0° C., and stirred at the sametemperature for 30 mins. Followed a standard aqueous/EtOAc workup andpurified by column chromatography (PE:EtOAc=10:1) to give product (560mg, 66% yield).

Step 2: Synthesis of methyl 4-formyl-2-(trifluoromethyl)benzoate

To a mixture of the compound from step 1 (500 mg, 1.6 mmol) in MeOH (20mL) and DMF (5 mL) was added Pd(OAc)₂ (10 mg, 0.05 mmol), dppf (10 mg,0.02 mmol) and TEA (2 drops) under argon atmosphere. The suspension wasdegassed under vacuum and purged with carbon monoxide for several times.Then the mixture was stirred at 70° C. under carbon monoxide atmosphere(40 psi) for 12 hours. The mixture was filtered through a pad of Celiteand the filter cake was washed with EtOAc. The solvent was removed invacuo. Purified crude by column chromatography (PE:EtOAc=10:1) to giveIntermediate 82 (180 mg, yield 38%).

Intermediate 83: methyl 2-fluoro-4-formyl-6-hydroxybenzoate Step 1:Synthesis of 2-fluoro-4-formyl-6-methoxyphenyl trifluoromethanesulfonate

Followed the procedure described in Intermediate 82, Step 1 to giveproduct, 61% yield.

Step 2: Synthesis of methyl 2-fluoro-4-formyl-6-methoxybenzoate

A mixture of the compound from above (step 1) (1.1 g, 3.6 mmol),Pd(OAc)₂ (200 mg, 0.89 mmol), dppf (200 mg, 0.36 mmol) and Et₃N (2 mL)in MeOH (50 mL) and DMF (2 mL) was stirred under CO atmosphere (50 psi)at 80° C. overnight. The resulting mixture was cooled and filtered. Astandard aqueous/EtOAc workup was followed by purification by columnchromatography on silica gel (PE:EtOAc=15:1) to give product as anoff-white solid (280 mg, yield 36%).

Step 3: Synthesis of methyl 2-fluoro-4-formyl-6-hydroxybenzoate

Followed procedure described in Intermediate 65, step 3 where reactionwas complete after refluxing 5 min. Product was taken on crude withoutpurification (250 mg, yield 96%).

Intermediate 84: methyl 4-formyl-2-hydroxybenzoate Step 1: Synthesis of4-formyl-2-methoxyphenyl trifluoromethanesulfonate

Followed the procedure described in Intermediate 82, Step 1, whereaddition occurred at room temperature, and reaction was run at sametemperature for 1 h. Isolated product as oil (17.0 g, yield 91%).

Step 2: Synthesis of methyl 4-formyl-2-methoxybenzoate

Followed the procedure described in Intermediate 83, Step 2, to giveproduct as a colorless solid (2.6 g, yield 76%).

Step 3: Synthesis of methyl 4-formyl-2-hydroxybenzoate

Followed procedure described in Intermediate 65, step 3 where reactionwas complete after refluxing 5 min. Product was taken on crude withoutpurification (2.2 g, yield 92%).

Intermediate 85: methyl 2-ethoxy-4-formyl-6-hydroxybenzoate Step 1:Synthesis of ethyl 4-bromo-3,5-diethoxybenzoate

Described in Step 1 of Int. 76.

Step 2: Synthesis of (4-bromo-3,5-diethoxyphenyl)methanol

Followed the procedure described in Step 6 of Int. 76 to give a whitesolid (4.2 g, yield 98%).

Step 3: Synthesis of methyl 2,6-diethoxy-4-(hydroxymethyl)benzoate

Followed the procedure described in Intermediate 83, Step 2, exceptreaction was stirred under CO atmosphere (5 MPa) at 120° C. for 3 days.Isolated product after column as an off-white solid (1.0 g, 36%).

Step 4: Synthesis of methyl 2,6-diethoxy-4-formylbenzoate

Followed Step 7 of Intermediate 76 where reaction was refluxed 1 hour.Product (950 mg, yield 96%) was isolated after workup.

Step 5: Synthesis of methyl 2-ethoxy-4-formyl-6-hydroxybenzoate

Followed procedure described in Intermediate 65, step 3 where reactionwas complete after stirring at 10° C. for 5 minutes. Isolated productafter column chromatography as off-white solid (500 mg, yield 59%).

Intermediate 86: methyl 2-chloro-4-formyl-6-hydroxybenzoate

Followed the three step procedure described for preparing Intermediate84, starting from 3-chloro-4-hydroxy-5-methoxybenzaldehyde.

Step 1: 2-chloro-4-formyl-6-methoxyphenyl trifluoromethanesulfonate

1.9 g, yield 56%.

Step 2: methyl 2-chloro-4-formyl-6-methoxybenzoate

370 mg, yield 52%.

Step 3: methyl 2-chloro-4-formyl-6-hydroxybenzoate

290 mg, yield 84%.

Intermediate 87: methyl 4-formyl-2-hydroxy-6-methoxybenzoate

Followed the procedure described for Intermediate 85, steps 3, 4, and 5.

Step 1: methyl 4-(hydroxymethyl)-2,6-dimethoxybenzoate

Isolated 750 mg, yield 20%.

Step 2: methyl 4-formyl-2,6-dimethoxybenzoate

Isolated 700 mg, yield 94%.

Step 3: methyl 4-formyl-2-hydroxy-6-methoxybenzoate

Isolated 500 mg, yield 82%.

Intermediate 88: 1-(1-methyl-1H-pyrazol-4-yl)-2-phenylethanone Step 1:Synthesis of N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide

Followed the procedure described in Step 1 of Intermediate 7, startingfrom 1-methyl-1H-pyrazole-4-carboxylic acid, with the followingdeviation: the reaction was run at 9-17° C. overnight. Isolated 4.6 g,yield 69%.

Step 2: Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)-2-phenylethanone

Followed the procedure described in Step 2 of Intermediate 22, with thefollowing deviation: crude was purified by silica gel columnchromatography (PE:EtOAc=10:1) (4.0 g, yield 74%).

Intermediate 89:3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrobenzaldehyde Step 1:Synthesis of 3-(2-(dimethylamino)ethoxy)-4-methoxybenzaldehyde

To a solution of 2-(dimethylamino)ethanol (5.0 g, 56.0 mmol) andtriethylamine (8.5 g, 84.0 mmol) in anhydrous DCM (50 mL) was addedmethanesulfonyl chloride (7.1 g, 62.0 mmol) at 0° C. under N₂. Themixture was stirred at 0° C. for 1 hour The solvent was removed in vacuo(6.0 g, yield 65%), and the crude was taken up in CH₃CN (100 mL).3-hydroxy-4-methoxybenzaldehyde (5.5 g, 36.0 mmol) and potassiumcarbonate (13.8 g, 100.0 mol) was added and reaction was refluxed underN₂ overnight. An aqueous/EtOAc workup was followed, and crude waspurified by silica gel column chromatography (PE: EtOAc=3:1) to giveproduct (2.5 g, yield 31%) as yellow solid.

Step 2: Synthesis of 3-(2-(dimethylamino)ethoxy)-4-hydroxybenzaldehyde

Followed the procedure described in Intermediate 65, step 3 where thereaction was refluxed for 2 days. Column chromatography (PE:EtOAc=3:1)gave product (620 mg, yield 66%).

Step 3: Synthesis of3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrobenzaldehyde

Followed procedure for Intermediate 59 to give Intermediate 89 (250 mg,34%) as a yellow solid.

Intermediate 90: 2-phenyl-1-(tetrahydrofuran-2-yl)ethanone Step 1:Synthesis of N-methoxy-N-methyltetrahydrofuran-2-carboxamide

Followed the procedure described in Intermediate 10, Step 1, startingwith tetrahydrofuran-2-carboxylic acid to give product (680 mg, yield:49.7%).

Step 2: Synthesis of 2-phenyl-1-(tetrahydrofuran-2-yl)ethanone

Followed the procedure described in Intermediate 22, Step 2 to giveIntermediate 90, 520 mg, yield: 63.9%.

Intermediate 91: 1-cyclopentyl-2-phenylethanone

To a solution of titanium(IV) isopropoxide (5.13 mmol, 1.46 g) inanhydrous tetrahydro-furan (10 mL) was added a solution ofcyclopentylmagnesium chloride in THF (7.69 mmol) at −78° C. Reaction waswarmed to −50° C. in 5 min, then maintained at that temperature for 8min and reaction became dark-brown to black. After cooling back to −78°C., 2-phenylacetonitrile (600 mg, 5.13 mmol) was added by a syringe, andthe mixture was stirred at −78° C. for 2 h. 1 N HCl aqueous solution wasadded to quench the reaction. The mixture was extracted with acetic acidethyl ester (40 mL) for three times, the combined organic layer waswashed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography to giveIntermediate 91 (320 mg, yield: 66.5%) as light green oil.

Intermediate 92: 2-phenyl-1-(tetrahydrofuran-3-yl)ethanone Step 1:Synthesis of N-methoxy-N-methyltetrahydrofuran-3-carboxamide

Followed the procedure described in Intermediate 10, Step 1, startingwith tetrahydrofuran-3-carboxylic acid to give product (0.8 g, yield29.6%) as an oil.

Step 2: Synthesis of 2-phenyl-1-(tetrahydrofuran-3-yl)ethanone

Followed the procedure described in Intermediate 22, Step 2, where crudewas purified by column chromatography (PE:EtOAc=15:1) on silica gel togive Intermediate 92 (130 mg, yield 54.6%) as an oil.

Intermediate 93: (S)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone Step 1:Synthesis of (S)—N-methoxy-N-methyltetrahydrofuran-2-carboxamide

Followed the procedure described in Intermediate 10, Step 1, startingwith (S)-tetrahydrofuran-2-carboxylic acid to give product (1.2 g, yield42%).

Step 2: Synthesis of (S)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone

Followed the procedure described in Intermediate 22, Step 2 with apurification by silica gel column chromatography (eluting fromPE:EtOAc=20:1 to PE:EtOAc=5:1) to give Intermediate 93 (460 mg, yield67%).

Intermediate 94: (R)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone Step 1:Synthesis of (R)—N-methoxy-N-methyltetrahydrofuran-2-carboxamide

Followed the procedure described in Intermediate 10, Step 1, startingwith (R)-tetrahydrofuran-2-carboxylic acid to give product (1.2 g, yield44%).

Step 2: Synthesis of (R)-2-phenyl-1-(tetrahydrofuran-2-yl)ethanone

Followed the procedure described in Intermediate 22, Step 2 with apurification by silica gel column chromatography (eluting fromPE:EtOAc=20:1 to PE:EtOAc=5:1) to give Intermediate 94 (400 mg, yield56%).

Intermediate 95: 1-cyclohexyl-2-(thiophen-3-yl)ethanone Step 1:Synthesis of cyclohexanecarbonyl chloride

Followed the procedure described in Step 1 of Intermediate 56, startingwith cyclohexanecarboxylic acid.

Step 2: Synthesis of ethyl3-cyclohexyl-3-oxo-2-(thiophen-3-yl)propanoate

Followed the procedure described in Step 2 of Intermediate 56. Usedcrude from step 1 and ethyl 2-(thiophen-3-yl)acetate. Crude product wastaken forward without purification.

Step 3: Synthesis of 1-cyclohexyl-2-(thiophen-3-yl)ethanone

Followed the procedure described in Step 3 of Intermediate 56.

Intermediate 96: 2-cyclohexyl-1-phenylethanone

To a suspension of Mg (735 mg, 30.5 mmol) in anhydrous THF (20 mL) wasadded (bromomethyl)cyclohexane (5.4 g, 30.5 mmol) at 10° C. under N₂atmosphere. The resulting mixture was stirred at reflux until all of Mgwas consumed. Then the resulting mixture was cooled to ambienttemperature and N-methoxy-N-methylbenzamide (1.0 g, 6.1 mmol) was addedand the mixture was stirred at 10° C. for 2 hours. The mixture wasquenched with aqueous saturated NH₄Cl (50 mL). Followed a standardaqueous/EtOAc workup and the residue was purified by columnchromatography on silica gel (PE:EtOAc=20:1) to give Intermediate 96 ascolorless oil (800 mg, yield 67%).

Example 179 GSNOR Assays

Various compounds were tested in vitro for their ability to inhibitGSNOR activity. GSNOR inhibitor compounds in Examples 1-87, 89-91, 93,95-103, 105-170, 172-177 had an IC₅₀ of about <100 μM. GSNOR inhibitorcompounds in Examples 1, 2, 4-13, 15-17, 20-23, 26, 28-39, 43-61, 63,65, 67, 69, 71, 73, 77-81, 83-86, 95, 101-102, 105-116, 118-121,125-139, 141-143, 146-148, 150-152, 154-156, 158-161, 163, 165, 167,169, 170, 172-175, and 177 had an IC₅₀ of about <1.0 μM. GSNOR inhibitorcompounds in Examples 1, 2, 4-6, 9, 13, 15-17, 20-21, 23, 29, 31-39,43-51, 53, 55-57, 61, 63, 65, 67, 71, 73, 78-79, 81, 83, 101-102,107-109, 111, 113, 115-116, 118-121, 125, 129-139, 141-143, 146, 148,155-156, 158-159, 161, 163, 165, 167, 169, 172, 174, and 177 had an IC₅₀of about less than 0.1 μM. GSNOR expression and purification isdescribed in Biochemistry 2000, 39, 10720-10729.

GSNOR Fermentation:

Pre-cultures were grown from stabs of a GSNOR glycerol stock in 2XYTmedia containing 100 ug/ml ampicillin after an overnight incubation at37° C. Cells were then added to fresh 2XYT (4 L) containing ampicillinand grown to an OD (A₆₀₀) of 0.6-0.9 at 37° C. before induction. GSNORexpression was induced with 0.1% arabinose in an overnight incubation at20° C.

GSNOR Purification:

E. coli cell paste was lysed by nitrogen cavitation and the clarifiedlysate purified by Ni affinity chromatography on an AKTA FPLC (AmershamPharmacia). The column was eluted in 20 mM Tris pH 8.0/250 mM NaCl witha 0-500 mM imidazole gradient. Eluted GSNOR fractions containing theSmt-GSNOR fusion were digested overnight with Ulp-1 at 4° C. to removethe affinity tag then re-run on the Ni column under the same conditions.GSNOR was recovered in the flowthrough fraction and for crystallographyis further purified by Q-Sepharose and Heparin flowthroughchromatography in 20 mM Tris pH 8.0, 1 mM DTT, 10 uM ZnSO₄.

GSNOR assay:

GSNO and Enzyme/NADH Solutions are made up fresh each day. The Solutionsare filtered and allowed to warm to room temperature. GSNO Solution: 100mM NaPO4 (pH 7.4), 0.480 mM GSNO. 396 μL of GSNO Solution is added to acuvette followed by 8 μL of test compound in DMSO (or DMSO only for fullreaction control) and mixed with the pipette tip. Compounds to be testedare made up at a stock concentration of 10 mM in 100% DMSO. 2 foldserial dilutions are done in 100% DMSO. 8 μL of each dilution are addedto an assay so that the final concentration of DMSO in the assay is 1%.The concentrations of compounds tested range from 100 to 0.003 μM.Enzyme/NADH Solution: 100 mM NaPO4 (pH 7.4), 0.600 mM NADH, 1.0 μg/mLGSNO Reductase. 396 μL of the Enzyme/NADH Solution is added to thecuvette to start the reaction. The cuvette is placed in the Cary 3EUV/Visible Spectrophotometer and the change in 340 nm absorbance/min at25° C. is recorded for 3 minutes. The assays are done in triplicate foreach compound concentration. IC₅₀'s for each compound are calculatedusing the standard curve analysis in the Enzyme Kinetics Module ofSigmaPlot.

Final assay conditions: 100 mM NaPO4, pH 7.4, 0.240 mM GSNO, 0.300 mMNADH, 0.5 μg/mL GSNO Reductase and 1% DMSO. Final volume: 800μL/cuvette.

Example 180 Efficacy of GSNORi in experimental asthma ExperimentalAsthma Model

A mouse model of ovalbumin (OVA)-induced asthma is used to screen GSNORinhibitors for efficacy against methacholine (MCh)-inducedbronchoconstriction/airway hyper-reactivity. This is a widely used andwell characterized model that presents with an acute, allergic asthmaphenotype with similarities to human asthma. Efficacy of GSNORinhibitors are assessed using a prophylactic protocol in which GSNORinhibitors are administered prior to challenge with MCh.Bronchoconstriction in response to challenge with increasing doses ofMCh is assessed using whole body plethysmography (P_(enh); Buxco). Theamount of eosinophil infiltrate into the bronchoaveolar lavage fluid(BALF) is also determined as a measure of lung inflammation. The effectof GSNOR inhibitors are compared to vehicles and to Combivent (inhaled;IH) as the positive control.

Materials and Method

Allergen Sensitization and Challenge Protocol

OVA (500 μg/ml) in PBS is mixed with equal volumes of 10% (w/v) aluminumpotassium sulfate in distilled water and incubated for 60 min. at roomtemperature after adjustment to pH 6.5 using 10 N NaOH. Aftercentrifugation at 750×g for 5 min, the OVA/alum pellet is resuspended tothe original volume in distilled water. Mice receive an intraperitoneal(IP) injection of 100 μg OVA (0.2 mL of 500 μg/mL in normal saline)complexed with alum on day 0. Mice are anesthetized by IP injection of a0.2-mL mixture of ketamine and xylazine (0.44 and 6.3 mg/mL,respectively) in normal saline and are placed on a board in the supineposition. Two hundred fifty micrograms (100 μl of a 2.5 mg/ml) of OVA(on day 8) and 125 μg (50 μl of 2.5 mg/ml) OVA (on days 15, 18, and 21)are placed on the back of the tongue of each animal.

Pulmonary Function Testing (Penh)

In vivo airway responsiveness to methacholine is measured 24 h after thelast OVA challenge in conscious, freely moving, spontaneously breathingmice with whole body plethysmography using a Buxco chamber (Wilmington,N.C.). Mice are challenged with aerosolized saline or increasing dosesof methacholine (5, 20 and 50 mg/mL) generated by an ultrasonicnebulizer for 2 min. The degree of bronchoconstriction is expressed asenhanced pause (P_(enh)), a calculated dimensionless value, whichcorrelates with the measurement of airway resistance, impedance, andintrapleural pressure in the same mouse. P_(enh) readings are taken andaveraged for 4 min. after each nebulization challenge. P_(enh) iscalculated as follows: P_(enh)=[(T_(e)/T_(r)−1)×(PEF/PIF)], where T_(e)is expiration time, T_(r) is relaxation time, PEF is peak expiratoryflow, and PIF is peak inspiratory flow×0.67 coefficient. The time forthe box pressure to change from a maximum to a user-defined percentageof the maximum represents the relaxation time. The T_(r) measurementbegins at the maximum box pressure and ends at 40%.

Eosinophil Infiltrate in BALF

After measurement of airway hyper-reactivity, the mice are exsanguinatedby cardiac puncture, and then BALF is collected from either both lungsor from the right lung after tying off the left lung at the mainstembronchus. Total BALF cells are counted from a 0.05 mL aliquot, and theremaining fluid is centrifuged at 200×g for 10 min at 4° C. Cell pelletsare resuspended in saline containing 10% BSA with smears made on glassslides. Eosinophils are stained for 5 min. with 0.05% aqueous eosin and5% acetone in distilled water, rinsed with distilled water, andcounterstained with 0.07% methylene blue.

GSNOR Inhibitors and Controls

GSNOR inhibitors are reconstituted in phosphate buffered saline (PBS),pH 7.4, at concentrations ranging from 0.00005 to 3 mg/mL. GSNORinhibitors are administered to mice (10 mL/kg) as a single dose eitherintravenously (IV) or orally via gavage. Dosing is performed from 30min. to 24 h prior to MCh challenge. Effect of GSNOR inhibitors arecompared to PBS vehicle dosed in the same manner.

Combivent is used as the positive control in all studies. Combivent(Boehringer Ingelheim) is administered to the lung using the inhalerdevice supplied with the product, but adapted for administration tomice, using a pipet tip. Combivent is administered 48 h, 24 h, and 1 hprior to MCh challenge. Each puff (or dose) of Combivent provides a doseof 18 μg ipatropium bromide (IpBr) and 103 μg albuterol sulfate orapproximately 0.9 mg/kg IpBr and 5 mg/kg albuterol.

Statistical Analyses

Area under the curve values for P_(enh) across baseline, saline, andincreasing doses of MCh challenge are calculated using GraphPad Prism5.0 (San Diego, Calif.) and expressed as a percent of the respective (IVor orally administered) vehicle control. Statistical differences amongtreatment groups and the respective vehicle control group within eachstudy are calculated using one-way ANOVA, Dunnetts (JMP 8.0, SASInstitute, Cary, N.C.). A p value of <0.05 among the treatment groupsand the respective vehicle control group is considered significantlydifferent.

Example 181 Mouse Pharmacokinetic (PK) Study Experimental Model

The mouse can be used to determine the pharmacokinetics of compounds ofthe invention. This species is widely used to assess the bioavailabilityof compounds by administering both oral (PO) and intravenous (IV) testarticles. Efficacy of the compounds of the invention can be compared byassessing plasma exposure in male BALB/c mice either via IV or POadministration at the times of peak activity.

Materials and Methods

IV Administration of Compounds of the Invention

Compounds of the invention can be reconstituted in a phosphate bufferedsaline (PBS)/10% Solutol (HS 15) clear solution resulting in aconcentration of 0.2 mg/mL and administered to mice (2 mg/kg) as asingle IV dose. Animals dosed via the lateral tail vein. Blood samplesare collected at designated time points (0.083, 0.25, 0.5, 1, 2, 4, 8,16, 24 hours) by cardiac puncture under isoflurane anesthesia (up to 1mL blood per animal). The blood is collected into tubes containingLi-Heparin. The blood samples are kept on ice until centrifugationwithin approximately 30 minutes of collection. The plasma is transferredinto labeled polypropylene tubes and frozen at −70° C. until analyzed byLC/MS/MS.

PO Administration of Compounds of the Invention

The compounds of the invention can be reconstituted in 40% PropyleneGlycol/40% Propylene Carbonate/20% of a 5% Sucrose clear solutionresulting in a concentration of 2 mg/mL and administered to mice (10mg/kg) as a single oral dose via gavage. Blood samples are collected at0.25, 0.5, 1, 2, 4, 8, 12, 16, 20 and 24 hours post dose by cardiacpuncture under isoflurane anesthesia. The blood is collected in tubescontaining Li-Heparin. The blood samples are kept on ice untilcentrifugation within approximately 30 minutes of collection. The plasmais transferred into labeled polypropylene tubes and frozen at −70° C.until analyzed by LC/MS/MS.

LC/MS/MS Analysis

Plasma samples at each timepoint can be analyzed using a LC-MS/MS with alower limit of quantification (LLOQ) of 1 ng/mL. Plasma is analyzed todetermine the amount of the compound of the invention in each sample andregression curves generated for each compounds of the invention in therelevant matrixes.

WinNonlin analysis is used for calculating PK parameters for both the IVand PO administrations:

PK parameters for IV portion—AUC_(last); AUC_(INF); T1/2; Cl; Vss;C_(max); MRT

PK parameters for PO portion—AUC_(last); AUC_(INF); T1/2; C_(max); Cl,MRT.

In addition to the above PK parameters, bioavailability (% F) can becalculated.

Example 182 Efficacy of GSNOR Inhibitors in Experimental InflammatoryBowel Disease (IBD) Experimental Model

An acute model of dextran sodium sulfate (DSS)-induced IBD in mice isused to explore efficacy of GSNOR inhibitors against this disease. AcuteDSS-induced IBD is a widely used and well characterized model thatinduces pathological changes in the colon similar to those observed inthe human disease. In this model and in human disease, epithelial cellswithin the crypts of the colon are disrupted, leading to dysfunction ofthe epithelial barrier and the ensuing tissue inflammation, edema, andulceration. GSNOR inhibitor therapy may benefit IBD by restorings-nitrosogluthathione (GSNO) levels, and thus prevent or reverse theepithelial barrier dysfunction.

Experimental IBD is induced by administration of DSS in the drinkingwater over several days. GSNOR inhibitors are administered daily viaintravenous (IV) dosing. Effect of treatment is assessed via endoscopyand histopathology using a five point scale ranging from a score=0(normal tissue) to a score=4 (ulcerative tissue damage and markedpathological changes). The effect of GSNOR inhibitors is compared tovehicle treated controls. The corticosteroid, prednisolone, is used asthe positive control in this study and is administered daily via oraldosing. Naïve mice are also assessed as a normal tissue control.

Materials and Methods

Experimental IBD is induced by administration of 3% DSS in the drinkingwater on study days 0 to 5. GSNOR inhibitors are reconstituted toconcentrations of 0.2 and 2 mg/ml in phosphate buffered saline (PBS), pH7.4. Mice are treated daily via IV administration of 0.1 ml GSNORinhibitor solution per mouse for doses of 1 and 10 mg/kg/day. GSNORinhibitor dosing is started 2 days prior to the DSS administration andcontinued through the last day of the study (days −2 to 7). PBS is usedas the vehicle control and is administered in the same manner as theGSNOR inhibitor. The corticosteroid, prednisolone, is used as thepositive control for the study, and is administered orally at a dose of3 mg/kg/day on each day (study days −2 to 7).

The effect of drug treatment is assessed on day 7 via endoscopy andhistopathology. Mice are first anesthetized with inhaled isoflurane andsubjected to endoscopy using a veterinary endoscope (Karl StorzVeterinary Endoscopy America, Inc., Goleta, Calif.). Each mouse isscored for mucosal injury using the endoscopy scoring criteria. Anendoscopy score of 0 is normal, 1 is loss of vascularity, 2 is loss ofvascularity and friability, 3 is friability and erosions, and 4 isulcerations and bleeding. Following endoscopy, mice are euthanized viaasphyxiation with inhaled carbon dioxide. Colon sections are thenformalin-fixed, paraffin-embedded, sectioned, and stained withhematoxylin-eosin. Colon sections are examined via light microscopy andscored in a blinded fashion by a board certified veterinary pathologistwith particular expertise in GI pathology. Pathological changes to theepithelium, connective tissue, and submucosa are scored based oninflammation, edema, and necrosis, and a score of 0 is normal, 1 isminimal, 2 is mild, 3 is moderate, and 4 is marked.

Example 183 Efficacy of GSNOR Inhibitors in Experimental ChronicObstructive Pulmonary Disease (COPD) Experimental COPD Model

An acute model of elastase-induced COPD in mice is used to exploreefficacy of GSNOR inhibitors against this disease. Elastase-induced COPDis a widely used and well characterized model that induces pathologicalchanges in the lung similar to those observed in the human disease. Inthis model and in human disease, airway obstruction, pulmonaryinflammation, and airspace enlargement are evident. GSNOR inhibitortherapy may benefit COPD through the bronchodilatory andanti-inflammatory actions of these compounds.

Experimental COPD is induced by administration of the elastases, papainand porcine pancreatic elastase (PPE), into the lung over several days.GSNOR inhibitors are administered daily via oral dosing. Efficacy isdetermined by assessing the ability of GSNOR inhibitors to attenuatebronchoconstriction in response to methacholine (MCh) aerosol challenge,decrease pulmonary inflammation, and reduce airspace enlargement in theaveoli. The effect of GSNOR inhibitors are compared to vehicle treatedcontrols. A combination of daily oral SP CXC receptor 2/receptor 1 (SPCXCR2/1) antagonist, which blocks recruitment of neutrophils andmonocytes, and inhaled Flovent (fluticasone; corticosteroid), is used asthe positive control in this study.

Materials and Methods

Experimental COPD is induced by administration of 80 μg papain and 20U/mg PPE per mouse per day via intra-tracheal (IT) instillation on studydays 0 to 7. GSNOR inhibitor is reconstituted to concentrations of 0.01,0.1, and 1 mg/ml in phosphate buffered saline (PBS), pH 7.4. Mice aretreated daily via oral administration (gavage) of 0.1 ml GSNORi solutionper mouse for doses of 0.1, 1, and 10 mg/kg/day. PBS is used as thevehicle control and is administered via daily oral dosing. The smallmolecule antagonist SP CXCR2/R1 (Schering-Plough/Merck), which blocksreceptors to cytokine chemoattractants for neutrophil and monocyterecruitment, is used in combination with the corticosteroid, Flovent(Glaxo), as the positive control for the study. SP CXCR2/R1 is dosedorally at 50 mg/kg/day. Flovent is dosed via inhalation at 220μg/mouse/day. One group of mice is treated with GSNOR inhibitor, vehiclecontrol, or positive control for 7 days (study days 8 to 14), while asecond group of mice is treated with GSNOR inhibitor, vehicle control,or positive control for 14 days (study days 8 to 21).

The effect of drug treatment is assessed 7 and 14 days post-treatment bymeasuring attenuation of methacholine-induced bronchoconstriction(bronchodilatory effect), attenuation of pulmonary inflammation, andreduction of airspace enlargement in the alveoli (14 day post-treatmentonly).

Bronchodilatory Effect

In vivo airway responsiveness to methacholine is measured in conscious,freely moving, spontaneously breathing mice with whole bodyplethysmography using a Buxco chamber (Wilmington, N.C.). Mice arechallenged with aerosolized saline or increasing doses of methacholine(5, 20, and 50 mg/ml) generated by an ultrasonic nebulizer for 2 min.The degree of bronchoconstriction is expressed as enhanced pause (Penh),a calculated dimensionless value, which correlated with the measurementof airway resistance, impedance, and intrapleural pressure in the samemouse. Penh readings are taken and averaged for 4 min. after eachnebulization challenge. Penh is calculated as follows:Penh=[(T_(e)/T_(r)−1)×(PEF/PIF)], where T_(e) is expiration time, T_(r)is relaxation time, PEF is peak expiratory flow, and PIF is peakinspiratory flow×0.67 coefficient. The time for the box pressure tochange from a maximum to a user-defined percentage of the maximumrepresented the relaxation time. The T_(r) measurement began at themaximum box pressure and ended at 40%.

Anti-Inflammatory Effect

After measurement of airway hyper-reactivity, the mice areexsanguination by cardiac puncture, and then bronchoalveolar lavagefluid (BALF) is collected from the right lung after tying off the leftlung at the mainstem bronchus. Total BALF cells are counted, and theremaining fluid is centrifuged at 200×g for 10 min. at 4° C. Cellpellets are resuspended in saline containing 10% bovine serum albumin(BSA) and smears are made on glass slides using cytospin. Cells arestained with Diff-Quik for white blood cell (WBC) differential countsvia light microscopy. Epithelial cells are counted and subtracted fromthe total number of cells. The proportions of eosinophils, macrophages,neutrophils, and lymphocytes are counted using standard morphologicalcriteria and expressed as a percentage of the total number of whiteblood cells (WBCs).

The ability of treatment to reduce levels of neutrophil and monocytechemoattractants in the BALF are also assessed as additional parametersof anti-inflammatory effect. KC (keratinocyte chemoattractant), alsoknown as GROα (growth-related oncogene alpha), and JE (MCP-1, monocytechemoattractant protein), chemokines for neutrophil and monocyterecruitment, respectively, are measured using immunoassay.

Reduction of Airspace Enlargement

Both lungs are inflated under constant positive pressure at 25 cm waterpressure with 10% buffered formaldehyde and then perfused-fixed. Thefixed lungs are embedded in paraffin, stained with hematoxylin andeosin, and examined via light microscopy. Airspace enlargement isquantified morphologically by calculating the mean linear intercept (Lm)and average equivalent diameter of alveoli (D2).

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention.

The invention claimed is:
 1. A method of treatment of inflammation whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein X is selected from the group consisting of aryl, substitutedaryl, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, and substituted heterocyclyl, each having 6members or less in the ring; Y is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl, C₄-C₆cycloalkyl, substituted C₄-C₆ cycloalkyl, heterocyclyl, and substitutedheterocyclyl; Z is selected from the group consisting of O, S and NR₇;R₁, R₂ and R₇ are independently selected from the group consisting ofhydrogen, and C₁-C₆ alkyl; R₃ is selected from the group consisting ofhydrogen, nitro, cyano, carboxy, carbamoyl, methylsulfonamido, fluoro,chloro, bromo, hydroxy, methylsulfonyl, and methylsulfinyl,isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl; R₄is selected from the group consisting of hydroxy, carboxy, andtetrazol-5-yl; R₅ is selected from the group consisting of hydrogen,hydroxy, carboxy, chloro, fluoro, cyano, —O(CH₂)₁₋₆NMe₂, C₁-C₆ alkyl,—O(CH₂)₁₋₆OCH₃, —O(CH₂)₁₋₆OH, acetyl, CF₃, and C₁-C₆ alkoxy; and R₆ isselected from the group consisting of hydrogen and hydroxy.
 2. Themethod of claim 1 wherein R₁, R₂ and R₇ are independently selected fromthe group consisting of hydrogen and methyl; R₃ is selected from thegroup consisting of hydrogen, nitro, cyano, carboxy, carbamoyl,methylsulfonamido, fluoro, chloro, bromo, methylsulfonyl, andmethylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid,and acetyl; R₄ is selected from the group consisting of hydroxy,carboxy, and tetrazol-5-yl; R₅ is selected from the group consisting ofhydrogen, hydroxy, carboxy, chloro, fluoro, cyano, —O(CH₂)₂NMe₂, C₁-C₆alkyl, —O(CH₂)₂OCH₃, —O(CH₂)₂OH, acetyl, CF₃, methoxy, ethoxy,isopropoxy, and n-propoxy; and R₆ is hydrogen.
 3. The method of claim 1wherein X is selected from the group consisting of phenyl, substitutedphenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substitutedthiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl, andsubstituted pyridin-yl, cyclohexyl, and substituted cyclohexyl.
 4. Themethod of claim 1 wherein X is selected from the group consisting ofphenyl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, 2-fluorophenyl,p-tolyl, m-tolyl, biphenyl-4-yl, 4-methoxyphenyl, 3-chlorophenyl,3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-bromophenyl,o-tolyl, 4-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl,3,4-difluorophenyl, 4-cyanophenyl, 3-carbamoylphenyl, pyrazin-2-yl,biphenyl-3-yl, 2-cyanophenyl, pyridin-4-yl, and pyridin-3-yl,4-(dimethylamino)phenyl, 3-fluorophenyl, 3-ethylphenyl, and cyclohexyl.5. The method of claim 1 wherein Y is selected from the group consistingof phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl,thiazol-yl, substituted thiazol-yl, pyrazin-yl, substituted pyrazin-yl,pyridin-yl, substituted pyridin-yl, furan-yl, substituted furan-yl,benzo[d][1,3]dioxol-yl, substituted benzo[d][1,3]dioxol-yl, imidazol-yl,substituted imidazol-yl, naphthalen-yl, substituted naphthalen-yl,pyrrol-yl, substituted pyrrol-yl, pyrazol-yl, substituted pyrazol-yl,tetrahydrofuran-yl, substituted tetrahydrofuran-yl, cyclopentyl,substituted cyclopentyl, cyclohexyl, and substituted cyclohexyl.
 6. Themethod of claim 1 wherein Y is selected from the group consisting ofphenyl, 3-methoxyphenyl, p-tolyl, 4-methoxyphenyl, 3,5-dichlorophenyl,3-fluorophenyl, 4-bromophenyl, biphenyl-4-yl, 4-fluorophenyl,4-chlorophenyl, 3-chlorophenyl, 3,4-dimethoxyphenyl,3-fluoro-4-methoxyphenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3,4-dichlorophenyl, 4-hydroxyphenyl, 2,4-difluorophenyl, furan-3-yl,2-chlorophenyl, 3-cyanophenyl, 4-(dimethylamino)phenyl, 2-fluorophenyl,4-morpholinophenyl, 4-aminophenyl, naphthal-2-yl,benzo[d][1,3]dioxol-5-yl, 4-cyanophenyl, naphthal-3-yl, naphthal-4-yl,4-acetamidophenyl, thiophen-2-yl, thiophen-3-yl,1-methyl-1H-imidazol-4-yl, naphthalene-1-yl, methyl phenylcarbamate, andnaphthalene-2-yl, 4-(methanesulfonamido)phenyl, 1H-pyrrol-3-yl,1-(phenylsulfonyl)-1H-pyrrol-3-yl, furan-2-yl,4-(trifluoromethyl)phenyl, o-tolyl, 1-methyl-1H-pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 3-chloro-5-fluorophenyl, 3-hydroxyphenyl,pyrazin-2-yl, quinolin-6-yl, isoquinolin-6-yl, 1-methyl-1H-pyrazol-5-yl,tetrahydrofuran-2-yl, cyclopentyl, tetrahydrofuran-3-yl, and cyclohexyl.7. The method of claim 1 wherein the compound of Formula (I) orpharmaceutically acceptable salt thereof is selected from the groupconsisting of4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione;4-(4-hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3,4-dihydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(2-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-m-tolyl-3,4-dihydropyrimidin-2(1H)-one;5-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;5-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;5-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,5-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluoro-4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1,3-dimethyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;6-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3-chloro-4-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,5-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-3-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide;3-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;6-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(2-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-morpholinophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyrazin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;5-(biphenyl-3-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(benzo[d][1,3]dioxol-5-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-3-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;4-(3-ethoxy-5-fluoro-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;2-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)acetamide;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;N-(3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;N-(2-hydroxy-3-methoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-imidazol-4-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-1-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide;methyl4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenylcarbamate;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-hydroxy-3-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;5-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;1,1′-(2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-1,3-phenylene)diethanone;4-(4-hydroxy-3-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-bromo-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;4-(4-hydroxy-3-isopropoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-(methylsulfonyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-(methylsulfinyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-6-phenyl-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;2-ethoxy-4-(2-imino-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(Z)-2-ethoxy-4-(2-(methylimino)-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-chloro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3-chloro-5-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonicacid;(S)-3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-fluoro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-nitro-5-propoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyrazin-2-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(quinolin-6-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(isoquinolin-6-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(5-(3-methoxyphenyl)-2-oxo-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-(2-hydroxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-5-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-ethylphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-chloro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-hydroxy-3-nitro-5-(trifluoromethyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-(2-methoxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-nitro-5-propylphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoicacid;2-fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-hydroxy-4-(2-oxo-5-phenyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-ethoxy-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-(2H-tetrazol-5-yl)phenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-chloro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-(2H-tetrazol-5-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-6-methoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-(2H-tetrazol-5-yl)phenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid; 4-(3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;6-cyclopentyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-3-yl)-3,4-dihydropyrimidin-2(1H)-one;6-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((S)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((R)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;and5-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one.8. The method of claim 1 comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I)or a pharmaceutically acceptable salt thereof together with apharmaceutically accepted carrier or excipient.
 9. A method of treatmentof inflammatory bowel disease (IBD) which comprises administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof:

wherein X is selected from the group consisting of aryl, substitutedaryl, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, and substituted heterocyclyl, each having 6members or less in the ring; Y is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl, C₄-C₆cycloalkyl, substituted C₄-C₆ cycloalkyl, heterocyclyl, and substitutedheterocyclyl; Z is selected from the group consisting of O, S and NR₇;R₁, R₂ and R₇ are independently selected from the group consisting ofhydrogen, and C₁-C₆ alkyl; R₃ is selected from the group consisting ofhydrogen, nitro, cyano, carboxy, carbamoyl, methylsulfonamido, fluoro,chloro, bromo, hydroxy, methylsulfonyl, and methylsulfinyl,isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl; R₄is selected from the group consisting of hydroxy, carboxy, andtetrazol-5-yl; R₅ is selected from the group consisting of hydrogen,hydroxy, carboxy, chloro, fluoro, cyano, —O(CH₂)₁₋₆NMe₂, C₁-C₆ alkyl,—O(CH₂)₁₋₆OCH₃, —O(CH₂)₁₋₆OH, acetyl, CF₃, and C₁-C₆ alkoxy; and R₆ isselected from the group consisting of hydrogen and hydroxy.
 10. A methodof making a pharmaceutical composition comprising the step of combininga compound of formula I:

wherein X is selected from the group consisting of aryl, substitutedaryl, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, and substituted heterocyclyl, each having 6members or less in the ring; Y is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl, C₄-C₆cycloalkyl, substituted C₄-C₆ cycloalkyl, heterocyclyl, and substitutedheterocyclyl; Z is selected from the group consisting of O, S and NR₇;R₁, R₂ and R₇ are independently selected from the group consisting ofhydrogen, and C₁-C₆ alkyl; R₃ is selected from the group consisting ofhydrogen, nitro, cyano, carboxy, carbamoyl, methylsulfonamido, fluoro,chloro, bromo, hydroxy, methylsulfonyl, and methylsulfinyl,isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl; R₄is selected from the group consisting of hydroxy, carboxy, andtetrazol-5-yl; R₅ is selected from the group consisting of hydrogen,hydroxy, carboxy, chloro, fluoro, cyano, —O(CH₂)₁₋₆NMe₂, C₁-C₆ alkyl,—O(CH₂)₁₋₆OCH₃, —O(CH₂)₁₋₆OH, acetyl, CF₃, and C₁-C₆ alkoxy; R₆ isselected from the group consisting of hydrogen and hydroxyl, with apharmaceutically accepted carrier or excipient.
 11. The method of claim9 wherein R₁, R₂ and R₇ are independently selected from the groupconsisting of hydrogen and methyl; R₃ is selected from the groupconsisting of hydrogen, nitro, cyano, carboxy, carbamoyl,methylsulfonamido, fluoro, chloro, bromo, methylsulfonyl, andmethylsulfinyl, isoxazol-4-yl, C₁-C₆ alkoxy, —C(NH)NHOH, sulfonic acid,and acetyl; R₄ is selected from the group consisting of hydroxy,carboxy, and tetrazol-5-yl; R₅ is selected from the group consisting ofhydrogen, hydroxy, carboxy, chloro, fluoro, cyano, —O(CH₂)₂NMe₂, C₁-C₆alkyl, —O(CH₂)₂OCH₃, —O(CH₂)₂OH, acetyl, CF₃, methoxy, ethoxy,isopropoxy, and n-propoxy; and R₆ is hydrogen.
 12. The method of claim 9wherein X is selected from the group consisting of phenyl, substitutedphenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substitutedthiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl, andsubstituted pyridin-yl, cyclohexyl, and substituted cyclohexyl.
 13. Themethod of claim 9 wherein X is selected from the group consisting ofphenyl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, 2-fluorophenyl,p-tolyl, m-tolyl, biphenyl-4-yl, 4-methoxyphenyl, 3-chlorophenyl,3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-bromophenyl,o-tolyl, 4-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl,3,4-difluorophenyl, 4-cyanophenyl, 3-carbamoylphenyl, pyrazin-2-yl,biphenyl-3-yl, 2-cyanophenyl, pyridin-4-yl, and pyridin-3-yl,4-(dimethylamino)phenyl, 3-fluorophenyl, 3-ethylphenyl, and cyclohexyl.14. The method of claim 9 wherein Y is selected from the groupconsisting of phenyl, substituted phenyl, thiophen-yl, substitutedthiophen-yl, thiazol-yl, substituted thiazol-yl, pyrazin-yl, substitutedpyrazin-yl, pyridin-yl, substituted pyridin-yl, furan-yl, substitutedfuran-yl, benzo[d][1,3]dioxol-yl, substituted benzo[d][1,3]dioxol-yl,imidazol-yl, substituted imidazol-yl, naphthalen-yl, substitutednaphthalen-yl, pyrrol-yl, substituted pyrrol-yl, pyrazol-yl, substitutedpyrazol-yl, tetrahydrofuran-yl, substituted tetrahydrofuran-yl,cyclopentyl, substituted cyclopentyl, cyclohexyl, and substitutedcyclohexyl.
 15. The method of claim 9 wherein Y is selected from thegroup consisting of phenyl, 3-methoxyphenyl, p-tolyl, 4-methoxyphenyl,3,5-dichlorophenyl, 3-fluorophenyl, 4-bromophenyl, biphenyl-4-yl,4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dimethoxyphenyl,3-fluoro-4-methoxyphenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3,4-dichlorophenyl, 4-hydroxyphenyl, 2,4-difluorophenyl, furan-3-yl,2-chlorophenyl, 3-cyanophenyl, 4-(dimethylamino)phenyl, 2-fluorophenyl,4-morpholinophenyl, 4-aminophenyl, naphthal-2-yl,benzo[d][1,3]dioxol-5-yl, 4-cyanophenyl, naphthal-3-yl, naphthal-4-yl,4-acetamidophenyl, thiophen-2-yl, thiophen-3-yl,1-methyl-1H-imidazol-4-yl, naphthalene-1-yl, methyl phenylcarbamate, andnaphthalene-2-yl, 4-(methanesulfonamido)phenyl, 1H-pyrrol-3-yl,1-(phenylsulfonyl)-1H-pyrrol-3-yl, furan-2-yl,4-(trifluoromethyl)phenyl, o-tolyl, 1-methyl-1H-pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 3-chloro-5-fluorophenyl, 3-hydroxyphenyl,pyrazin-2-yl, quinolin-6-yl, isoquinolin-6-yl, 1-methyl-1H-pyrazol-5-yl,tetrahydrofuran-2-yl, cyclopentyl, tetrahydrofuran-3-yl, and cyclohexyl.16. The method of claim 9 wherein the compound of Formula (I) orpharmaceutically acceptable salt thereof is selected from the groupconsisting of4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione;4-(4-hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3,4-dihydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(2-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-m-tolyl-3,4-dihydropyrimidin-2(1H)-one;5-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;5-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;5-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;5-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,5-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluoro-4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1,3-dimethyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;6-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3-chloro-4-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,5-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-3-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide;3-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;6-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(2-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-morpholinophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyrazin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;5-(biphenyl-3-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;6-(benzo[d][1,3]dioxol-5-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-3-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;4-(3-ethoxy-5-fluoro-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;2-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)acetamide;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;N-(3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;N-(2-hydroxy-3-methoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-imidazol-4-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-1-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide;methyl4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenylcarbamate;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-hydroxy-3-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;5-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;1,1′-(2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-1,3-phenylene)diethanone;4-(4-hydroxy-3-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-bromo-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;4-(4-hydroxy-3-isopropoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-(methylsulfonyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-(methylsulfinyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-6-phenyl-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;2-ethoxy-4-(2-imino-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;(Z)-2-ethoxy-4-(2-(methylimino)-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-chloro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;6-(3-chloro-5-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonicacid;(S)-3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-fluoro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-nitro-5-propoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyrazin-2-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(quinolin-6-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(isoquinolin-6-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(5-(3-methoxyphenyl)-2-oxo-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-(2-hydroxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-5-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-ethylphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-chloro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-hydroxy-3-nitro-5-(trifluoromethyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-(2-methoxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(4-hydroxy-3-nitro-5-propylphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoicacid;2-fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-hydroxy-4-(2-oxo-5-phenyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;2-ethoxy-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-(2H-tetrazol-5-yl)phenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-chloro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-(2H-tetrazol-5-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-6-methoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;4-(4-(2H-tetrazol-5-yl)phenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid;(S)-2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoicacid; 4-(3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;6-cyclopentyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-3-yl)-3,4-dihydropyrimidin-2(1H)-one;6-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((S)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((R)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;and5-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one.17. The method of claim 9 comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I)or a pharmaceutically acceptable salt thereof together with apharmaceutically accepted carrier or excipient.